Stabilized hme composition with small drug particles

ABSTRACT

A hot-melt extruded composition having finely divided drug-containing particles dispersed within a polymeric and/or lipophyllic carrier matrix is provided. The carrier softens or melts during hot-melt extrusion but it does not dissolve the drug-containing particles during extrusion. As a result, a majority or at least 90% wt. of the drug-containing particles in the extrudate are deaggregated during extrusion into essentially primary crystalline and/or amorphous particles. PEO is a suitable carrier material for drugs insoluble in the solid state in this carrier. Various functional excipients can be included in the carrier system to stabilize the particle size and physical state of the drug substance in either a crystalline and/or amorphous state. The carrier system is comprised of at least one thermal binder, and may also contain various functional excipients, such as: super-disintegrants, antioxidants, surfactants, wetting agents, stabilizing agents, retardants, or similar functional excipients. A hydrophilic polymer, such as hydroxypropyl methylcellulose (HPMC E15), polyvinyl alcohol (PVA), or poloxamer, and/or a surfactant, such as sodium lauryl sulfate (SLS), can be included in the composition. A process for preparing the extrudate is conducted at a temperature approximating or above the softening or melting temperature of the matrix and below the point of solubilization of drug-containing particles in the carrier system, and below the recrystallization point in the case of amorphous fine drug particles.

This application is a continuation of U.S. application Ser. No.11/718,620, filed Nov. 19, 2007, which is a national phase applicationunder 35 U.S.C. §371 of International Application No PCT/US2005/040535filed Nov. 9, 2005, which claims priority to U.S. provisionalapplication No. 60/681,279, filed May 16, 2005, and U.S. provisionalapplication No. 60/626,400, filed Nov. 9, 2005. The entire text of eachof the above referenced disclosures is specifically incorporated hereinby reference.

FIELD OF THE INVENTION

The present invention concerns a hot-melt extruded pharmaceuticalcomposition comprising a therapeutic compound dispersed as fineparticles in a stabilizing and non-solubilizing carrier system and amethod of preparation thereof. The invention also concerns a process ofpreparing a hot-melt extruded pharmaceutical composition wherein smallamorphous or crystalline particles of a therapeutic compound aredispersed as individual particles during hot-melt extrusion and afterstorage for extended periods of time. The hot-melt extruded compositionprovides stable release properties of the therapeutic compound over anextended period of storage.

BACKGROUND OF THE INVENTION

Many researchers have utilized hot-melt extrusion techniques to producepharmaceutical preparations in various forms. Zhang and McGinityutilized hot-melt extrusion to produce sustained release matrix tabletswith PEO and polyvinyl acetate, and more generally non-film preparationswith polyethylene oxide (PEO) (1-3). Kothrade et al. demonstrated amethod of producing solid dosage forms of active ingredients in avinyllactam co-polymeric binder by hot-melt extrusion (4). Aitken-Nicholet al. used hot-melt extrusion methods to produce acrylic polymer filmscontaining the active lidocaine HCl (5). Grabowski et al. produced solidpharmaceutical preparations of actives in low-substituted hydroxypropylcellulose using hot-melt extrusion techniques (6). Repka and McGinityused hot-melt extrusion processes to produce bioadhesive films fortopical and mucosal adhesion applications for controlled drug deliveryto various mucosal sites (7, 8). Robinson et al. produced effervescentgranules with controlled rate of effervescence using hot melt extrusiontechniques (3). Breitenbach and Zettler produced solid sphericalmaterials containing biologically active substances via hot-meltextrusion (9). De Brabander et al. demonstrated sustained releasemini-matrices by utilizing hot-melt extrusion techniques (10, 11).

Pharmaceutical formulations comprised of active compounds finely andhomogenously dispersed in one or more polymeric carriers have beendescribed as solid dispersions, glass solutions, molecular dispersions,and solid solutions. The term solid dispersion has been used as ageneral term to describe pharmaceutical preparations in which the activecompound is dispersed in an inert excipient carrier in a size range fromcourse to fine. Glass solution, molecular dispersion, and solid solutionrefer specifically to preparations in which amorphous forms of acrystalline active compound are formed in-situ and dispersed within thepolymer matrix during the hot-melt extrusion process.

Many researchers have produced such preparations with various activecompounds and polymeric carriers using hot-melt extrusion techniques.Rosenberg and Breitenbach have produced solid solutions by meltextruding the active substance in a nonionic form together with a saltand a polymer, such as polyvinylpyrrolidone (PVP),vinylpyrrolidinone/vinylacetate (PVPVA) copolymer, or ahydroxyalkylcellulose (12). Six et al., Brewster et al., Baert et al.,and Verreck et al. have produced solid dispersions of itraconazole withimproved dissolution rates by hot-melt extrusion with various polymericcarriers including hydroxypropylmethylcellulose, Eudragit E100, PVPVA,and a combination of Eudragit E100 and PVPVA (13-19). Rambaldi et al.produced solid dispersions of itraconazole by hot-melt extrusion withhydroxypropyl-beta-cyclodextrin and hydroxypropylmethylcellulose for theimprovement of aqueous solubility (20). Verreck et al. produced soliddispersions of a water-insoluble microsomal triglyceride transferprotein inhibitor with improved bioavailability by hot-melt extrusion(21). Hulsmann et al. produced solid dispersions of the poorly watersoluble drug 17 β-estradiol with increased dissolution rate by hot meltextrusion with polymeric carriers such as polyethylene glycol, PVP, andPVPVA along with various non-polymeric additives (22). Forster et al.produced amorphous glass solutions with the poorly water soluble drugsindomethacin, lacidipine, nifedipine, and tolbutamide in PVP and PVPVAdemonstrating improved dissolution compared with the crystalline forms(23). In this article, it is also seen that after storage of theextrudates at 25° C. and 75% relative humidity only compositionscontaining indomethacin and polymer in a one to one ratio remainedcompletely amorphous. Formulations of the remaining drugs andformulations with increased indomethacin concentration showedrecrystallization on storage. This recrystallization was shown tosignificantly decrease the dissolution rate of the active. It shouldalso be noted that stability studies were not performed at elevatedtemperatures in this study. It would be expected that elevatedtemperatures would increase the occurrence and extent ofrecrystallization.

The previous reference reveals the inherent instability of amorphousdispersions produced by hot-melt extrusion techniques. Although manyarticles demonstrate the production of amorphous solid dispersions andthe resulting improvement of drug dissolution rate, very few discuss thestability of such preparations on storage. From the work of Foster etal. and an understanding of the thermodynamics of amorphous systems, itcan be concluded that recrystallization of amorphous solid dispersionformulations on storage is a common problem. The amorphous state isthermodynamically metastable, and therefore it is expected thatamorphous compounds will assume a stable crystalline conformation withtime, as well as in response to perturbations such as elevations intemperature and exposure to moisture. In an extruded formulation,amorphous drug particles will agglomerate and crystallize withincreasing storage time, elevated temperature, or exposure to moisture,essentially precipitating out of the carrier. This progression towardsphase separation during storage results in a time dependant dissolutionprofile. A change in dissolution rate with time precludes the successfulcommercialization of a pharmaceutical product.

The article by Foster et al. also demonstrates the limitation of drugloading in amorphous solid dispersions by hot-melt extrusion. It is seenin this article that recrystallization of indomethacin on storage isinduced when the concentration of indomethacin is increased from 1:1 to4:1 drug to polymer ratio. Six et al. demonstrated immiscibility ofitraconazole and Eudragit E100 when extruded at 140° C. and phaseseparation on processing at concentrations greater than 13% and 20%(w/w) when extruded at 168° C. and 180° C., respectively (14-16). Six etal. also demonstrated a single phase system of itraconazole and PVPVA atdrug concentrations up to 80% (w/w), however only a slight improvementof the dissolution rate was achieved (16). Kearney et al. showed phaseseparation of an anti-inflammatory drug, CI-987, in PVP at drugconcentrations greater than 19% (w/w) for solid dispersions prepared bysolvent evaporation methods (24). Verreck et al. demonstrated anamorphous dispersion of itraconazole in HPMC at a concentration of 40%drug, with improved dissolution rate and chemical and physical stabilityfor up to 6 months at various temperature and humidity conditions (17).In a follow up article, Six et al. showed phase separation ofitraconazole from identical HPMC carrier systems at a concentration of60% drug (13).

The difficulty of producing stable single phase amorphous dispersions ofhigh drug loading can be seen from references such as those given above.The appearance of a second phase of the active compound on processing oron storage would result in a time dependent biphasic dissolutionprofile, and would therefore not be considered an acceptablepharmaceutical preparation.

Although there have been many reports of successful production of soliddispersions by hot-melt extrusion that show improved dissolution ratesof poorly water soluble drugs, the absence of numerous marketed productsbased on this technology is evidence that stability problems remain amajor obstacle for successful commercialization of such a pharmaceuticalpreparation.

There are several methods well known in the pharmaceutical literaturefor producing fine drug particles in the micro or nanometer size range.These methods can be divided into three primary categories: (1)mechanical micronization (2) solution based phase separation and (3)rapid freezing techniques.

Mechanical micronization is most commonly done by milling techniquesthat can produce particles in the range of 1 to 20 microns. The mostcommon processes utilized for this type of mechanical particle sizereduction are ball and jet milling. Milling drug particles by theseprocesses can reduce primary drug particles to micron-sized particles,however high surface energy results in aggregation of primary particleswhich to an extent negates the milling process. Nykamp et al. andCarstensen et al. demonstrated a melt grinding and jet milling techniqueto produce drug loaded microparticles of polylactic acid orpolylactic-co-glycolic acid with mean particle size in the range of fourto six microns (25, 26).

There are many solution based phase separation processes documented inthe pharmaceutical literature for producing micro and nano-sized drugparticles. Some of the more commonly known processes are spray drying,emulsification/evaporation, emulsification/solvent extraction, andcomplex coacervation. Some of the lesser-known processes are, for thesake of brevity, listed below along with their respective illustratingreferences: a) gas antisolvent precipitation (GAS)—(27) and WO9003782EPO437451 EPO437451 DK59091; b) precipitation with a compressedantisolvent (PCA)—(28) and U.S. Pat. No. 5,874,029; c) aerosol solventextraction system (ASES)—(29); d) evaporative precipitation into aqueoussolution (EPAS)—(30) US patent application 20040067251; e) supercriticalantisolvent (SAS)—(31); f) solution-enhanced dispersion by supercriticalfluids (SEDS)—(32); g) rapid expansion from supercritical to aqueoussolutions (RESAS)—(33); and h) anti-solvent precipitation.

Freezing techniques for producing micro or nano-sized drug particles arelisted below along with their respective illustrating references: a)spray freezing into liquid (SFL)—(34) WO02060411 USPTO App. #2003054042and 2003024424; and b) ultra rapid freezing (URF)—(35).

It should be noted that fine drug particles produced by solution-basedphase separation or rapid freezing techniques are often amorphous innature. Theses amorphous particles can be stabilized by compelxation orcoating during the production process with one or more excipientcarriers having high melting points or glass transition temperatures.Stabilized amorphous fine drug particles can be formulated into thepresent preparation in the same manner as crystalline fine drugparticles. The high shear of the hot-melt extrusion process willeffectively deaggregate and disperse the amorphous drug particles(likely to be aggregated before extrusion due to high surface energy asstated in the next paragraph) into the stabilizing and non-solubilizingcarrier thereby separating the aggregated particles into primaryparticles that are stabilized against aggregation and agglomeration onprocessing and storage by the carrier system. The excipient system withwhich the amorphous drug particles are complexed or coated will preventrecrystallization during hot-melt extrusion and storage of the amorphousdrug-containing particle domains that are dispersed in the stabilizingand non-solubilizing carrier matrix. The benefit of this form of anamorphous dispersion compared to a traditional amorphous dispersion isthat the formation of fine amorphous drug particles is not dependent onthe solubility of the drug in the carrier system, since the amorphousdrug particles are not formed in situ by the solubilization of thecrystalline drug particles by the carrier system.

It has been reported that fine drug particles produced by processes suchas those listed above exhibit high surface energy resulting in strongcohesive forces between particles. Zimon showed that powders of fineparticles are likely to aggregate because the force of detachment isdependent on particle mass which is small in the case of fine particles(36). The forces of cohesion between individual fine particles aretherefore greater than the forces of detachment, and thus particleaggregates form. French et al. demonstrated that the forces of cohesionbetween particles increase with decreasing particle size (37).Therefore, the extent of aggregation is increased as particle size isreduced.

Aggregation of fine particles results in an increase in the apparentparticle size, consequently, particle size reduction is somewhatnegated. In order to achieve the full benefit of particle sizereduction, i.e. accelerated dissolution rate, aggregates must be reducedto individual particles when dosed. Lui and Stewart demonstrated areduction in dissolution rate of benzodiazepines with an increasingextent of particle aggregation (38).

Particle agglomeration with storage also causes an increase in apparentparticle size, and a corresponding decrease in dissolution rate.Ticehurst et al. demonstrated agglomeration of micronized revatropatehydrobromide when stored at greater than 25% relative humidity (39).Therefore, in the production of an ideal solid dosage form containingfine drug particles, aggregates would be separated and stabilized asindividual particles by a carrier system during processing. The carriersystem would also function to impede particle aggregation andagglomeration on storage at ambient and accelerated temperature andhumidity conditions.

There have been few published reports of the successful incorporation offine drug particles into a traditional dosage forms. Hu et al. developedan immediate release tablet of Danazol micronized powder by the SFLprocess, however only 5.3% drug loading was reported (40). Authors havealso reported on the oral delivery of fine drug particles in the form ofa stabilized liquid suspension (41, 42). There are two importantlimitations of delivering fine drug particle formulations in a liquidsuspension, namely the instability of the preparation and the commerciallimitation of shipping suspensions. Liquid suspensions are known to beunstable on storage due to agglomeration, and sedimentation, as well ascaking of suspended particles. Commercially it is not ideal to formulatea pharmaceutical preparation as a suspension due to the cost of shippingthe excess weight of the liquid vehicle, as compared to a solid dosageform.

Prior art examples such as those given above demonstrate the ongoingneed for the advantageous properties of the present invention for thedelivery of drug from a hot-melt extruded composition comprising finedrug particles.

SUMMARY OF THE INVENTION

The present invention seeks to overcome some or all of the disadvantagesinherent in the above-mentioned compositions and methods. The presentinvention allows for high drug loading of fine drug particles in astable and easily portable solid dosage form. In addition, thepreparation can be formulated to provide a variety of drug releaseprofiles to most sites of administration.

The present invention relates to pharmaceutical formulations comprisedof active compounds finely and homogenously dispersed in one or morepolymeric carriers that are produced by hot-melt extrusion techniques.Such preparations have been described as solid dispersions, glasssolutions, molecular dispersions, and solid solutions.

The composition herein may be formulated to avoid the problem of phaseseparation with increasing concentration by incorporating into thecarrier system crystalline fine drug particles or stabilized amorphousfine drug particles produced prior to extrusion. Additionally, bydispersing crystalline or stabilized, preformed amorphous fine drugparticles into the non-solubilizing, stabilizing carrier system via thehigh shear extrusion process, problems of recrystallization of amorphousdomains, as well as particle aggregation and agglomeration are overcome.

The present invention addresses the problem of physical instability oftraditional solid dispersions and the resulting time-dependent drugrelease profile by dispersing, via hot-melt extrusion, fine drugparticles in a thermodynamically stable crystalline state, or in astabilized amorphous state into a polymeric carrier which will act toseparate and isolate individual drug particles, thus preventingaggregation and agglomeration during processing and on storage. Thecarrier is formulated such that it will not substantially compromise theintegrity of the individual drug particles during extrusion, such as bydissolving all or a significant part of the drug particles.

This invention also relates to the field of fine particle technology inthat fine particles produced from any fine particle productiontechnology can be incorporated into the claimed pharmaceuticalpreparation.

The present invention can be formulated to achieve an advantageousdosage form comprising fine drug particles. Processing powders of finedrug particles with a stabilizing and non-solubilizing carrier system byhot-melt extrusion one or more times reduces particle aggregation andstabilizes them as individual fine drug particles. The resulting productis a solid dispersion of fine particles stabilized by the carriersystem, wherein the composition maintains primary particle integrity onstorage.

One aspect of the invention provides a hot-melt extruded pharmaceuticalcomposition comprising an effective amount of a therapeutic compounddispersed as fine particles in a stabilizing and non-solubilizingcarrier system. The fine drug-containing particles are dispersed withinthe carrier system via hot-melt extrusion as discrete particles in asize range of less than one hundred microns, less than twenty microns,or less than five microns. A substantial majority, e.g. at least 75%wt., of the particles are not agglomerated or aggregated by the hot-meltextrusion process used to prepare the composition. In other words, atleast 75% wt. of the particles are present in unagglomerated form.

Another aspect of the invention provides a method of preparing ahot-melt extruded pharmaceutical composition comprising finedrug-containing particles dispersed in a stabilizing andnon-solubilizing thermally processable carrier, the method comprisingthe steps of:

-   providing a charge of fine drug-containing particles of a    therapeutic compound;-   providing a charge of stabilizing and non-solubilizing hot-melt    extrudable carrier; and-   mixing and hot-melting extruding the charges to form the hot-melt    extruded pharmaceutical composition; wherein a substantial majority    of the fine drug particles are not agglomerated or aggregated as a    result of the step of hot-melt extruding.

The invention also provides a pharmaceutical solid dosage form having astabilized release profile, the dosage form comprising a hot-meltextruded pharmaceutical composition comprising fine drug particles of atherapeutic compound dispersed in a stabilizing and non-solubilizingcarrier.

In some embodiments, the stabilizing and non-solubilizing carrier ishot-melt extrudable meaning it can be hot-melt-extruded with nosignificant thermal degradation. The stabilizing and non-solubilizingcarrier can also be thermally processable, meaning it softens and meltsat the processing temperature with no significant thermal degradation.In some embodiments, a major portion of the stabilizing andnon-solubilizing carrier is selected from the group consisting ofpolyethylene oxide; polypropylene oxide; polyvinylpyrrolidone;polyvinylpyrrolidone-co-vinylacetate; acrylate and methacrylatecopolymers; polyethylene; polycaprolactone;polyethylene-co-polypropylene; alkylcelluloses such as methylcellulose;hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxybutylcellulose;hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose andhydroxypropyl methylcellulose; starches, pectins; polysaccharides suchas tragacanth, gum arabic, guar gum, sucrose sterate, xanthan gum,lipids, waxes, mono, di, and tri glycerides, cetyl alcohol, sterylalcohol. parafilm waxes and the like, hydrogenated vegetable and castoroil, glycerol monostearte, polyolefins including xylitol, mannitol, andSorbitol, alpha hydroxyl acids including citric and tartaric acid edipicacid meleaic acid malic acid, citric acid, enteric polymers such as CAP,HPMC AS, shellac, and a combination thereof. The stabilizing andnon-solubilizing carrier can further comprise surfactant carbohydrate, ahigh HLB surfactant, a low HLB surfactant, tablet excipient, filler,binder, disintegrant, super disintegrant, protein, peptide, enzyme,hormone, protein or a combination thereof. In some embodiments, thestabilizing and non-solubilizing carrier is selected from the groupconsisting of fixed oil, nonpolar vehicle, and water miscibleingredients including alcohols and glycols such as the PEGs (poly(ethylene glycol)) and PG (propylene glycol).

When provided as a pharmaceutical composition, the pharmaceuticalcomposition (or dosage form) can provide an immediate or rapid releaseof therapeutic compound after exposure to an environment of use.Alternatively or additionally, the pharmaceutical composition (or dosageform) can be adapted to provide an extended release of therapeuticcompound after exposure to an environment of use. Likewise, thepharmaceutical composition (or dosage form) can be adapted to provide adelayed release of therapeutic compound after exposure to an environmentof use.

A dosage form containing the pharmaceutical composition can be selectedfrom the group consisting of bead, tablet, pill, granulate, powder,capsule, tube, strand, cylinder, or film and can be further processedinto a powder, pellets, or powder coatings for application on varioussubstrates.

The pharmaceutical dosage form can be formulated, for example, fortransdermal, transmucosal, rectal, pulmonary, nasal, vaginal, ocular, orotic drug delivery, or as an implantable drug delivery device.

BRIEF DESCRIPTION OF THE FIGURES

The following figures form part of the present description and describeexemplary embodiments of the claimed invention. The skilled artisanwill, in light of these figures and the description herein, be able topractice the invention without undue experimentation.

FIGS. 1a and b depict cross-sectional front elevation of an exemplaryembodiment of a hot-melt extruded composition according the invention.

FIGS. 2a-2c, 3a-3c, 4a-4c, 5a-5c and 6a-6c depict electron micrographsof control and exemplary sample formulations prepared as describedherein.

FIGS. 2d, 3d, 4d, 5d, and 6d depict DSC thermograms for control andexemplary sample formulations prepared as described herein.

FIGS. 7-8 depict comparative drug release profiles for compositions ofthe invention before and after storage and drug release profiles for acomposition not made according to the invention.

FIG. 9 depicts DSC thermograms obtained according to Example 3 ofPVP-stabilized amorphous ITZ particles (Example 9), extrudatescontaining PVP-stabilized amorphous ITZ (Example 10), a physical mixtureof crystalline ITZ with the excipient components of Examples 9 and 10,PVP K25, and bulk crystalline ITZ.

FIG. 10 depicts X-ray diffraction patterns obtained according to Example11 for poloxamer 407:PEO (7:3) placebo extrudate, a physical mixture ofcrystalline ITZ with the excipient components of examples 9 and 10,extrudates containing PVP-stabilized amorphous ITZ (Example 10), bulkITZ, and PVP-stabilized amorphous ITZ (Example 9).

FIGS. 11a-11d depict SEM (scanning electron microscopy) images obtainedaccording to Example 2 for samples prepared according to Example 9 (FIG.11a ), a Poloxamer:PEO (7:3) placebo extrudate (FIG. 11b ), and samplesprepared according Example 10 (FIGS. 11c and 11d ).

FIG. 12 depicts comparative dissolution test (drug release) profilesobtained according to Example 12 for samples made according to Example10, samples made according to Example 9, and bulk ITZ.

FIG. 13 depicts comparative dissolution profiles obtained according toExample 4 for samples made according to Example 9 and Example 10 beforeand after storage at conditions of 40° C. and 75% relative humidity inaluminum induction sealed high density polyethylene bottles for a periodof two weeks.

FIG. 14 depicts DSC thermograms obtained according to Example 3 forsamples prepared according to Example 13, samples prepared according toExample 14, a physical mixture of crystalline CBM with the excipientcomponents of examples 13 and 14, and PVP K25.

FIG. 15 depicts X-ray diffraction patterns obtained according to Example11 for poloxamer 407:PEO (7:3) placebo extrudate, a physical mixture ofcrystalline CBM with the excipient components of Examples 13 and 14,samples produced according to Example 14, samples produced according toExample 13, and bulk CBM.

FIG. 16 depicts comparative dissolution profiles obtained according toExample 12 for samples made according to Example 13 and Example 14.

FIG. 17 depicts comparative dissolution profiles for samples madeaccording to Example 13 and Example 14 in which the amount of CBM addedto each dissolution vessel (200 mg/900 ml) was several times greaterthan the equilibrium saturation solubility.

FIG. 18 depicts comparative dissolution profiles for samples madeaccording to Example 13 and samples made according to Example 14 beforeand after storage according to Example 4 at conditions of 40° C. and 75%relative humidity in aluminum induction sealed high density polyethylenebottles for a period of two weeks.

FIG. 19 depicts DSC thermograms obtained according to Example 3 forsamples produced according to Example 15, HPMC E3, samples producedaccording to Example 16, a physical mixture of crystalline KCZ with theexcipient components of Examples 15 and 16, and bulk ketoconazole.

FIG. 20a-20b depict SEM images obtained according to Example 2 forsamples prepared according to Example 17 (FIG. 20a ) and Example 18(FIG. 20b ). The circles in FIG. 20b highlight some of the more apparentfine crystals of Danazol that are dispersed in the polymeric carriermatrix.

DETAILED DESCRIPTION OF THE INVENTION

The drug-containing particles do not undergo substantial aggregation oragglomeration during hot-melt extrusion and/or can be deaggregated toessentially primary particles during hot-melt extrusion due to theintense mixing and agitation that occurs during the process. In somecases, the extrudate may need to be processed more than one time throughthe extruder in order to provide the desired degree of deaggregation. Asused herein, the term “deaggregate”, as used in reference to thedrug-containing particles, means to reduce a loosely bound agglomerateto essentially its primary constituent particles. As used herein, theterm “to agglomerate” or “agglomeration”, as used in reference to thedrug-containing particles means individual particles form a largerparticle.

The fine drug-containing particles may be produced by one of manyprocesses well known in the pharmaceutical literature. Such processesinclude mechanical milling by ball mill, jet mill, or other similargrinding process; solution based phase separation techniques such asspray drying, emulsification/evaporation, emulsification/solventextraction, complex coacervation, anti-solvent precipitation, gasantisolvent precipitation (GAS), precipitation with a compressedantisolvent (PCA), aerosol solvent extraction system (ASES), evaporativeprecipitation into aqueous solution (EPAS), supercritical antisolvent(SAS), solution-enhanced dispersion by supercritical fluids (SEDS),rapid expansion from supercritical to aqueous solutions (RESAS),pressure induced phase separation (PIPS); or freezing techniques such asspray freezing into liquid (SFL) and ultra rapid freezing (URF).Detailed descriptions of these methods are included in references citedherein, the entire disclosures of which are hereby incorporated byreference.

Examples 6 and 7 below provide exemplary detailed procedures for thepreparation of fine drug-containing particles by SFL and EPAS,respectively.

The drug-containing particles can comprise one or more drugs alone or amixture of drug and one or more other adjunct stabilizers, such assorbitan esters, polyoxyethylene sorbitan fatty acid esters,polyoxyethylene alkyl ethers, poloxamers (polyethylene-polypropyleneglycol block copolymers), sucrose esters, sodium lauryl sulfate, oleicacid, lauric acid, vitamin E TPGS, polyoxyethylated glycolysedglycerides, dipalmitoyl phosphadityl choline, glycolic acid and salts,deoxycholic acid and salts, sodium fusidate, cyclodextrins, polyethyleneglycols, polyglycolyzed glycerides, polyvinyl alcohols, polyacrylates,polymethacrylates, polyvinylpyrrolidones, phosphatidyl choline andderivatives, and cellulose derivatives. Excipients such as these can beused as adjunct stabilizers to complex or coat fine particles in-situfor particle stabilization and/or improved wetting.

If materials other than drug are present in the drug-containingparticles, such materials can be present up to an amount of about orless than 90% wt., about or less than 50% wt., or about or less than 10%wt. of the weight of drug-containing particles present.

The drug present in the drug-containing particles can be crystalline oramorphous in form or a combination thereof. The form of the drug in thedrug-containing particle does not change substantially during hot-meltextrusion. This means that the extent of crystallinity or amorphousnessof the drug-containing particles remains substantially the same afterprocessing as it was before processing. Specifically, less than about 5%by weight of a crystalline charge of drug-containing particles is madeamorphous, and conversely less than about 5% by weight of an amorphouscharge of drug-containing particles is made crystalline by hot-meltextrusion when such process is conducted as described herein.

The drug-containing particles typically have a mean particle diameter(based on the volume size distribution when approximated to a sphere) ofabout 100 microns or less, about 50 microns or less, about 10 microns orless, or about 1 micron or less. In some embodiments, the finedrug-containing particles will be stabilized in the nanometer rangeaccording to their method of preparation. Fine drug-containing particlesproduced by mechanical means typically range in size from 20 to 1microns. Particles produced by solution-based phase separation or rapidfreezing techniques typically have mean particle diameters ranging from10 micrometers to 50 nanometers.

According to some embodiments of the invention, greater than 75% of thedrug-containing particles have an average diameter of less than about 20microns, 5 microns, or 1 micron depending on the method of preparationof the particles.

The loading of fine drug-containing particles in the hot-melt extrudedpreparation may be up to concentrations of 80%. The particles aredeaggregated and homogenously dispersed as primary particles into anon-solubilizing, stabilizing carrier system owing to the high shear ofthe hot-melt extrusion process.

The nature of the carrier is such that the fine drug particles are notsolubilized to a substantial degree in it during extrusion, i.e. thedrug particles are practically insoluble in the carrier system at theextrusion temperature. The carrier also acts to stabilize the finedrug-containing particles such that particle aggregation oragglomeration does not occur, or only an insignificant amount, i.e.,about 5% by number or less of the drug-containing particles, ofaggregation or agglomeration does not occur, on processing, or uponstorage at various temperature and relative humidity conditions.Therefore, 5% by number or less of the drug-containing particles arepresent in the composition in agglomerated form.

As used herein, the term “stabilizing and non-solubilizing carrier”refers to a material, or combination of materials, that is used as thematrix in which the drug-containing particles are dispersed duringhot-melt extrusion. A stabilizing and non-solubilizing carrier does notsolubilize, or solubilizes an insubstantial amount, e.g. about 10% wt.or less, of the drug-containing particles charged into the hot-meltextrusion apparatus. In addition, a stabilizing and non-solubilizingcarrier stabilizes the average particle size of the fine drug particlesby preventing or minimizing agglomeration and crystal growth onprocessing and storage.

The stabilizing and non-solubilizing carrier must be processable byhot-melt extrusion, meaning that the carrier must be able to melt and/orsoften sufficiently to permit processing by hot-melt extrusion withoutsubstantial degradation of the carrier or the drug-containing particles.As such, the stabilizing and non-solubilizing carrier can include athermal binder, a pressure softenable binder, or a combination thereof.

Exemplary thermal binders include: polyethylene oxide; polypropyleneoxide; polyvinylpyrrolidone; polyvinylpyrrolidone-co-vinylacetate;acrylate and methacrylate copolymers; polyethylene; polycaprolactone;polyethylene-co-polypropylene; alkylcelluloses such as methylcellulose;hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxybutylcellulose;hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose andhydroxypropyl methylcellulose; starches, pectins; polysaccharides suchas tragacanth, gum arabic, guar gum, and xanthan gum. One embodiment ofthe binder is poly(ethylene oxide) (PEO), which can be purchasedcommercially from companies such as the Dow Chemical Company, whichmarkets PEO under the POLY OX™ trademark exemplary grades of which caninclude WSR N80 having an average molecular weight of about 200,000;1,000,000; and 2,000,000.

Suitable grades of PEO can also be characterized by viscosity ofsolutions containing fixed concentrations of PEO, such as for example:

Viscosity Range POLYOX Aqueous Solution Water-Soluble Resin NF at 25°C., mPa · s POLYOX Water-Soluble Resin NF WSR N-10 30-50 (5% solution)POLYOX Water-Soluble Resin NF WSR N-80 55-90 (5% solution) POLYOXWater-Soluble Resin NF WSR N-750  600-1,200 (5% solution) POLYOXWater-Soluble Resin NF WSR-205 4,500-8,800 (5% solution) POLYOXWater-Soluble Resin NF WSR-1105 8,800-17,600 (5% solution) POLYOXWater-Soluble Resin NF WSR N-12K 400-800 (2% solution) POLYOXWater-Soluble Resin NF WSR N-60K 2,000-4,000 (2% solution) POLYOXWater-Soluble Resin NF WSR-301 1,650-5,500 (1% solution) POLYOXWater-Soluble Resin NF WSR 5,500-7,500 Coagulant (1% solution) POLYOXWater-Soluble Resin NF WSR-303 7,500-10,000 (1% solution)

Suitable thermal binders that may or may not require a plasticizerinclude, for example, EUDRAGIT™ RS PO, EUDRAGIT™ S100, Kollidon SR(poly(vinyl acetate)-co-poly(vinylpyrrolidone) copolymer), ETHOCEL™(ethylcellulose), HPC (hydroxypropylcellulose), cellulose acetatebutyrate, poly(vinylpyrrolidone) (PVP), poly(ethylene glycol) (PEG),poly(ethylene oxide) (PEO), poly(vinyl alcohol) (PVA), hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxyethylcellulose(HEC), sodium carboxymethyl-cellulose (CMC), dimethylaminoethylmethacrylate-methacrylic acid ester copolymer,ethylacrylate-methylmethacrylate copolymer (GA-MMA), C-5 or 60 SH-50(Shin-Etsu Chemical Corp.), cellulose acetate phthalate (CAP), celluloseacetate trimelletate (CAT), poly(vinyl acetate) phthalate (PVAP),hydroxypropylmethylcellulose phthalate (HPMCP), poly(methacrylateethylacrylate) (1:1) copolymer (MA-EA), poly(methacrylatemethylmethacrylate) (1:1) copolymer (MA-MMA), poly(methacrylatemethylmethacrylate) (1:2) copolymer, EUDRAGIT L-30-D™ (MA-EA, 1:1),EUDRAGIT L-100-55™ (MA-EA, 1:1), hydroxypropylmethylcellulose acetatesuccinate (HPMCAS), COATERIC™ (PVAP), AQUATERIC™ (CAP), and AQUACOAT™(HPMCAS), polycaprolactone, starches, pectins; polysaccharides such astragacanth, gum arabic, guar gum, and xanthan gum.

The stabilizing and non-solubilizing carrier may also contain variousfunctional excipients, such as: hydrophilic polymer, antioxidant,super-disintegrant, surfactant including amphiphilic molecules, wettingagent, stabilizing agent, retardant, similar functional excipient, orcombination thereof, and plasticizers including citrate esters,polyethylene glycols, PG, triacetin, diethylphthalate, castor oil, andothers known to those or ordinary skill in the art. Extruded materialmay also include acidifying agent, adsorbent, alkalizing agent,buffering agent, colorant, flavorant, sweetening agent, diluent,opaquant, complexing agent, fragrance, preservative or a combinationthereof.

Exemplary hydrophilic polymers which can be a primary or secondarypolymeric carrier that can be included in the composition includepoly(vinyl alcohol) (PVA), polyethylene-polypropylene glycol (e.g.POLOXAMER™), carbomer, polycarbophil, or chitosan. The “hydrophilicpolymers” of the present invention include one or more of hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxypropyl cellulose,hydroxyethyl cellulose, methylcellulose, natural gums such as gum guar,gum acacia, gum tragacanth, or gum xanthan, and povidone. “Hydrophilicpolymers” also include polyethylene oxide, sodium carboxymethycellulose,hydroxyethyl methyl cellulose, hydroxymethyl cellulose,carboxypolymethylene, polyethylene glycol, alginic acid, gelatin,polyvinyl alcohol, polyvinylpyrrolidones, polyacrylamides,polymethacrylamides, polyphosphazines, polyoxazolidines,poly(hydroxyalkylcarboxylic acids), carrageenate alginates, carbomer,ammonium alginate, sodium alginate, or mixtures thereof.

As used herein, the term “antioxidant” is intended to mean an agent thatinhibits oxidation and thus is used to prevent the deterioration ofpreparations by oxidation due to the presence of oxygen free radicals orfree metals in the composition. Such compounds include, by way ofexample and without limitation, ascorbic acid, ascorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene, hypophophorous acid,monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate andsodium metabisulfite and others known to those of ordinary skill in theart. Other suitable antioxidants include, for example, vitamin C, BHT,BHA, sodium bisulfite, vitamin E and its derivatives, propyl gallate ora sulfite derivative.

As used herein, the term “disintegrant” is intended to mean a compoundused in solid dosage forms to promote the disruption of a solid mass(layer) into smaller particles that are more readily dispersed ordissolved. Exemplary disintegrants include, by way of example andwithout limitation, starches such as corn starch, potato starch,pre-gelatinized and modified starches thereof, sweeteners, clays,bentonite, microcrystalline cellulose (e.g., Avicel™),carboxymethylcellulose calcium, croscarmellose sodium, alginic acid,sodium alginate, cellulose polyacrilin potassium (e.g., AMBERLITE™),alginates, sodium starch glycolate, gums, agar, guar, locust bean,karaya, pectin, tragacanth, crospovidone and other materials known toone of ordinary skill in the art. A superdisintegrant is a rapidlyacting disintegrant. Exemplary superdisintegrants include crospovidoneand low substituted HPC.

Suitable surfactants include Polysorbate 80, sorbitan monooleate, sodiumlauryl sulfate or others. Soaps and synthetic detergents may be employedas surfactants. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts. Suitable detergents includecationic detergents, for example, dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl and olefin sulfonates, alkyl, olefin, ether andmonoglyceride sulfates, and sulfosuccinates; nonionic detergents, forexample, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene)-block-poly(oxypropylene) copolymers; and amphotericdetergents, for example, alkyl β-aminopropionates and 2-alkylimidazolinequaternary ammonium salts; and mixtures thereof.

Wetting agent is an agent that decreases the surface tension of aliquid. Wetting agents would include alcohols, glycerin, proteins,peptides water miscible solvents such as glycols, hydrophilic polymersPolysorbate 80, sorbitan monooleate, sodium lauryl sulfate, fatty acidalkali metal, ammonium, and triethanolamine salts, dimethyl dialkylammonium halides, alkyl pyridinium halides, and alkylamine acetates;anionic detergents, for example, alkyl, aryl and olefin sulfonates,alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates;nonionic detergents, for example, fatty amine oxides, fatty acidalkanolamides, and poly(oxyethylene)-block-poly(oxypropylene)copolymers; and amphoteric detergents, for example, alkylβ-aminopropionates and 2-alkylimidazoline quaternary ammonium salts; andmixtures thereof.

For the purpose of the present invention, stabilizing agents arepolymers and excipients that do not solubilize the drug particlespreferably agents with high melting points or glass transitiontemperatures and/or agents with no or minimal affinity for the active.The excipients restrict the mobility of drug particles within thecarrier thereby reducing particle aggregation and agglomeration onprocessing and storage. Such excipients include cellulosic polymersincluding HPMC, HPC, methylcellulose; polyvinyl alcohol,polyvinylpyrrolidone, polyvinylpyrrolidone-co-vinyl acetate and othersknown to those of ordinary skill in the art.

Retardants are agents that are insoluble or slightly soluble polymerswith a Tg above 45° C., more preferably above 50° C. before beingplasticized by other agents in the formulation including other polymersand other excipients needed for processing. The excipients includewaxes, acrylics, cellulosics, lipids, proteins, glycols, and the like.

Under the conditions of the hot-melt extrusion process of the invention,the fine drug-containing particles are deaggregated and homogenouslydispersed such that they exist within the carrier as individualparticles having a median particle diameter size range of less than onehundred microns, or less than twenty microns, and or less than fivemicrons. The extrusion process may be performed once, or several timesin series to further deaggregate and disperse the drug particles.

The resulting product can be produced in the form of tubes, strands,cylinders, or films; and can be further processed to fine powders,granules, pellets, spheres, or tablets that are intended for oraldelivery. The resulting product can also be formulated for transdermal,transmucosal, rectal, pulmonary, nasal, vaginal, ocular, or otic drugdelivery as well as an implantable drug delivery device.

The solid dosage formulations of the invention can assume any shape orform known in the art of pharmaceutical sciences. The dosage form can bea sphere, tablet, bar, plate, paraboloid of revolution, ellipsoid ofrevolution or other one known to those of ordinary skill in the art. Thesolid dosage form can also include surface markings, cuttings, grooves,letters and/or numerals for the purposes of decoration, identificationand/or other purposes.

The resulting composition is characterized by the substantial absence ofagglomerated or aggregated fine drug-containing particles afterprocessing and after storage for extended times and at varioustemperature and humidity conditions.

The carrier and/or the additional functional excipients may beformulated as to provide a predetermined approximate release profileunder predetermined conditions. The drug can be released according to animmediate, fast melt, rapid, sustained, controlled, slow, pulsatile orextended, and optionally delayed, targeted or timed drug releaseprofile. The pharmaceutical composition may deliver one or more activeagents in an extended release manner, and mechanisms employed for suchdelivery can include active agent release that is pH-dependent orpH-independent; diffusion or dissolution controlled; pseudo-zero order(approximates zero-order release), zero-order, pseudo-first order(approximates first-order release), or first-order; or slow, delayed,timed or sustained release or otherwise controlled release. The releaseprofile for the active agent can also be sigmoidal in shape, wherein therelease profile comprises an initial slow release rate, followed by amiddle faster release rate and a final slow release rate of activeagent.

By “immediate release” is meant a release of an active agent to anenvironment over a period of seconds to no more than about 30 minutesonce release has begun and release begins within no more than about 2minutes after administration. An immediate release does not exhibit asignificant delay in the release of drug.

By “rapid release” is meant a release of an active agent to anenvironment over a period of 1-59 minutes or 0.1 minute to three hoursonce release has begun and release can begin within a few minutes afteradministration or after expiration of a delay period (lag time) afteradministration.

As used herein, the term “extended release” profile assumes thedefinition as widely recognized in the art of pharmaceutical sciences.An extended release dosage form will release drug at substantiallyconstant rate over an extended period of time or a substantiallyconstant amount of drug will be released incrementally over an extendedperiod of time. An extended release tablet generally effects at least atwo-fold reduction in dosing frequency as compared to the drug presentedin a conventional dosage form (e.g., a solution or rapid releasingconventional solid dosage forms).

By “controlled release” is meant a release of an active agent to anenvironment over a period of about eight hours up to about 12 hours, 16hours, 18 hours, 20 hours, a day, or more than a day. By “sustainedrelease” is meant an extended release of an active agent to maintain aconstant drug level in the blood or target tissue of a subject to whichthe device is administered. The term “controlled release”, as regards todrug release, includes the terms “extended release”, “prolongedrelease”, “sustained release”, or “slow release”, as these terms areused in the pharmaceutical sciences. An controlled release can beginwithin a few minutes after administration or after expiration of a delayperiod (lag time) after administration.

A slow release dosage form is one that provides a slow rate of releaseof drug so that drug is released slowly and approximately continuouslyover a period of 3 hr, 6 hr, 12 hr, 18 hr, a day, 2 or more days, aweek, or 2 or more weeks, for example.

A timed release dosage form is one that begins to release drug after apredetermined period of time as measured from the moment of initialexposure to the environment of use.

A targeted release dosage form generally refers to an oral dosage formthat designed to deliver drug to a particular portion of thegastrointestinal tract of a subject. An exemplary targeted dosage formis an enteric dosage form that delivers a drug into the middle to lowerintestinal tract but not into the stomach or mouth of the subject. Othertargeted dosage forms can delivery to other sections of thegastrointestinal tract such as the stomach, jejunum, ileum, duodenum,cecum, large intestine, small intestine, colon, or rectum.

By “delayed release” is meant that initial release of drug occurs afterexpiration of an approximate delay (or lag) period. For example, ifrelease of drug from an extended release composition is delayed twohours, then release of drug from begins at about two hours afteradministration of the composition, or dosage form, to a subject. Ingeneral, a delayed release is opposite an immediate release, whereinrelease of drug begins after no more than a few minutes afteradministration. Accordingly, the drug release profile from a particularcomposition can be a delayed-extended release or a delayed-rapidrelease. A “delayed-extended” release profile is one wherein extendedrelease of drug begins after expiration of an initial delay period. A“delayed-rapid” release profile is one wherein rapid release of drugbegins after expiration of an initial delay period.

A pulsatile release dosage form is one that provides pulses of highactive ingredient concentration, interspersed with low concentrationtroughs. A pulsatile profile containing two peaks may be described as“bimodal”.

A pseudo-first order release profile is one that approximates a firstorder release profile. A first order release profile characterizes therelease profile of a dosage form that releases a constant percentage ofan initial drug charge per unit time.

A pseudo-zero order release profile is one that approximates azero-order release profile. A zero-order release profile characterizesthe release profile of a dosage form that releases a constant amount ofdrug per unit time.

The resulting product may also be formulated to exhibit enhanceddissolution rate of a formulated poorly water soluble drug.

Due to the deaggregation of fine particles on processing to form primaryparticles that are stabilized by the carrier system, the composition ordosage form will generally possess a substantially stable releaseprofile during storage. As used herein, the term “stable releaseprofile” refers to a dosage form that provides approximately the samerelease profile for a drug over the period of time during which thedosage form is stored. More specifically, a stable release profile isone wherein a dosage form provides a first release profile after beingstored a short first period of time under a first set of conditions andprovides a second release profile after being stored a longer secondperiod of time under the same first set of conditions such that thefirst and second release profiles vary by no more than ±10%. Therefore,an unstable release profile is one wherein the first and second releaseprofiles are not approximately the same, i.e. vary by more than ±10%.

An example of a composition or formulation having a stable releaseprofile follows. Two tablets having the same formulation are made. Thefirst tablet is stored for one day under a first set of conditions, andthe second tablet is stored for four months under the same first set ofconditions. The release profile of the first tablet is determined afterthe single day of storage and the release profile of the second tabletis determined after the four months of storage. If the release profileof the first tablet is approximately the same as the release profile ofthe second tablet, then the tablet/film formulation is considered tohave a stable release profile.

Another example of a composition or formulation having a stable releaseprofile follows. Tablets A and B, each comprising a film compositionaccording to the invention, are made, and Tablets C and D, eachcomprising a film composition not according to the invention, are made.Tablets A and C are each stored for one day under a first set ofconditions, and tablets B and D are each stored for three months underthe same first set of conditions. The release profile for each oftablets A and C is determined after the single day of storage anddesignated release profiles A and C, respectively. The release profilefor each of tablet B and D is determined after the three months ofstorage and designated release profiles B and D, respectively. Thedifferences between release profiles A and B are quantified as are thedifferences between release profiles C and D. If the difference betweenthe release profiles A and B is less than the difference between releaseprofiles C and D, tablets A and B are understood to provide a stable ormore stable release profile.

FIG. 1a depicts a conceptual cross-sectional front elevation of anexemplary hot-melt extruded composition according to the inventionillustrating individualized fine drug particles homogenously dispersedin a stabilizing and non-solubilizing carrier system. FIG. 1billustrates the same formulation after storage in sealed containers at40° C. and 75% relative humidity. This figure represents the preventionor inhibition of particle aggregation or agglomeration on storage by thestabilizing carrier.

Visual inspection of exemplary compositions No. 1-No. 10 (Example 1) ofthe invention is conducted by SEM according to Example 2 or with theunaided eye. Some of the results are summarized below. Visual inspectionof the composition of the invention was conducted by SEM and the unaidedeye.

No. Transparency Surface Texture Color 1 Transparent Smooth Yellow 2Opaque Slightly textured White 3 Translucent Textured Light yellow 4Opaque Textured White 5 Translucent Coarse Light to opaque Yellow 6Opaque Coarse White 7 Opaque Smooth White 8 Opaque Slightly texturedWhite 9 Transparent Smooth Yellow 10 Opaque Slightly textured White

The opaque and white appearance of extrudates containing itraconazolesignifies that itraconazole is not solubilized by the carrier systemwhen hot-melt extruded at 100° C. Being that this opacity was seen foreach formulation, it can be concluded that each of the functionaladditives did not influence the solubility of itraconazole in PEO. Foreach of the other non-active formulations, the color and texture wasseen to be homogenous, indicating that each of the additives arecompatible with PEO when hot-melt extruded at 100° C. The appearance ofa non-homogeneous color distribution or surface texture would generallysignify aggregation and indicate immiscibility of the additive with PEO.

FIGS. 2a-2c depict SEM micrographs of micronized itraconazole (ITZ)(FIG. 2a ) having an average particle size of 2.5 microns, hot-meltextruded PEO (FIG. 2b ) having an average molecular weight of about200,000, and hot-melt extruded formulation No. 2 (FIG. 2c ). Initially,the ITZ shows some aggregation and/or agglomeration prior to hot-meltextrusion. However, during hot-melt extrusion the particles aredeagglomerated and/or deaggregated and not dissolved by the carrier.

FIG. 2d depicts a DSC thermogram for hot-melt extruded PEO and acomposition made according to formula No. 2. The melting point ofcrystalline itraconazole is known to be about 165° C. Thedrug-containing composition shows a melting point of 127.72° C. for ITZ,signifying the temperature at which crystalline itraconazole issolubilized in PEO. This indicates that ITZ is present in itscrystalline form in the extrudate, and it therefore is not solubilizedby PEO when hot-melt extruded at 100° C. It is thus shown that PEO is asuitable thermal binder for a stabilizing and non-solubilizing carriersystem for fine particles of itraconazole when hot-melt extruded at 100°C.

FIGS. 3a-3c depict SEM micrographs of HPMC E15 (FIG. 3a ) having anaverage viscosity of 5 cPs as a 2% w solution with water, hot-meltextruded PEO and HPMC (FIG. 3b ) according to formula No. 3, andhot-melt extruded formulation No. 4 (FIG. 3c ). It is shown in FIG. 3bthat HPMC is reduced in particle size and dispersed in a crystallineform throughout the PEO matrix indicating the miscibility of HPMC withPEO when hot-melt extruded at 100° C. When the ITZ is added, theextrudate now comprises readily identifiable particles of ITZ indicatingthat it is deggregated during hot-melt extrusion and that the HPMC/PEOcarrier does not solubilize the ITZ during extrusion. In fact, theparticles are deagglomerated and/or deaggregated by the carrier duringhot-melt extrusion.

FIG. 3d includes a DSC thermogram for the formulations of FIGS. 3b and3c . The drug-containing composition shows a melting point of 127.33° C.for ITZ meaning that ITZ is present in its crystalline form in theextrudate. This further demonstrates that ITZ is not solubilized by thePEO/HPMC carrier.

FIGS. 4a-4c depict SEM micrographs of PVA (FIG. 4a ) having an averagemolecular weight of about 30 to 200,000 g/mol, hot-melt extruded PEO andPVA (FIG. 4b ) according to Formulation No. 5, and hot-melt extrudedformulation No. 6 (FIG. 4c ). It is shown in FIG. 4b that HPMC isreduced in particle size and dispersed in a crystalline form throughoutthe PEO matrix indicating the miscibility of PVA with PEO when hot-meltextruded at 100° C. When the ITZ is added, the extrudate now comprisesreadily identifiable particles of ITZ indicating that it is deaggregatedduring hot-melt extrusion and not solubilized by the PEO/PVA carrierduring extrusion. As above, the particles are deagglomerated and/ordeaggregated by the carrier during hot-melt extrusion.

FIG. 4d includes a DSC thermogram for formulations of FIGS. 4b and 4c .The drug-containing composition shows a melting point of 125.99° C. forITZ, again indicating that ITZ is present in its crystalline form in theextrudate and is therefore not solubilized by the carrier system. Theslight depression of the melting point indicates that a small portion ofthe crystalline ITZ is solubilized by the carrier system below 127° C. Amajority of this amount of dissolved ITZ is solubilized in a narrowtemperature range near the solubilization point in this carrier system(125.99° C.). Therefore, it can be concluded that only a negligibleamount, i.e less than 5% by wt. of the loaded ITZ is solubilized by thePVA in the formulation during hot-melt extrusion at 100° C. Increasingthe ratio of PVA to ITZ above one to one may cause a greater extent ofITZ to become solubilized in the carrier system.

FIGS. 5a-5c depict SEM micrographs of sodium lauryl sulfate (SLS) (FIG.5a ), hot-melt extruded PEO and SLS (FIG. 5b ) according to FormulationNo. 7, and hot-melt extruded formulation No. 8 (FIG. 5c ). It is shownin FIG. 5b that SLS is reduced in particle size and dispersed throughoutthe PEO matrix indicating the miscibility of SLS with PEO when hot-meltextruded at 100° C. When the ITZ is added, the extrudate now comprisesreadily identifiable particles of ITZ indicating that it is deaggregatedduring hot-melt extrusion and the PEO/SLS carrier does not solubilizethe ITZ during extrusion. Again, the particles are deagglomerated and/ordeaggregated by the carrier during hot-melt extrusion.

FIG. 5d includes a DSC thermogram for formulations of FIGS. 5b and 5c .The drug-containing composition shows a melting point of 124.55° C. forITZ, again indicating that ITZ is present in its crystalline form in theextrudate and is therefore not solubilized by the carrier system. Theslight depression of the melting point indicates that a small portion ofthe crystalline ITZ is solubilized by the carrier system below 127° C.Most of this amount of dissolved ITZ is solubilized in a narrowtemperature range near the solubilization point in this carrier system(124.55° C.). Therefore, it can be concluded that only a negligibleamount, i.e less than 5% by wt. of the loaded ITZ is solubilized by theSLS in the formulation during hot-melt extrusion at 100° C. Accordingly,embodiments of the invention wherein the carrier phase includes one ormore components that solubilize a portion of the drug hot-melt extrusioninclude those components in amounts insufficient to solubilize asubstantial amount of the drug during hot-melt extrusion. For example,such components are present in an amount such that less than 10% by wt.,less than 5% by wt. or less than 1% by wt. of the drug can solubilizeduring hot-melt extrusion.

FIGS. 6a-6c depict SEM micrographs of poloxamer 407 (FIG. 6a ) having anaverage molecular weight of about 9,840 to 14,600 g/mol, hot-meltextruded PEO and poloxamer (FIG. 6b ) according to Formulation No. 9,and hot-melt extruded formulation No. 10 (FIG. 6c ). The poloxamer andPEO form a substantially homogeneous extrudate indicating completemiscibility when hot-melt extruded at 100° C. When the ITZ is added, theextrudate now comprises readily identifiable particles of ITZ indicatingthat it is deaggregated during hot-melt extrusion and the PEO/poloxamercarrier does not solubilize the ITZ during extrusion. Again, theparticles are deagglomerated and/or deaggregated by the carrier duringhot-melt extrusion.

FIG. 6d includes a DSC thermogram for formulations of FIGS. 6b and 6c .The drug-containing composition shows a melting point of 124.18° C. forITZ, again indicating that ITZ is present in its crystalline form in theextrudate, and is therefore not solubilized by the carrier system. Theslight depression of the melting point indicates that a small portion ofthe crystalline ITZ is solubilized by the carrier system below 127° C.Most of this amount of dissolved ITZ is solubilized in a narrowtemperature range near the solubilization point in this carrier system(124.18° C.). Therefore, it can be concluded that only a negligibleamount, i.e less than 5 w of the loaded ITZ is solubilized by thepoloxamer in the formulation during hot-melt extrusion at 100° C.

The above-described results indicate that the hot-melt extrudatescomposed of PEO and poloxamer formed a homogeneous polymer matrix whenmelt extruded at 100° C. Further, compositions containing HPMC, PVA, orSLS were observed to have homogenously dispersed particles throughoutthe PEO matrix following melt extrusion.

Upon visual inspection it was determined that the addition ofitraconazole to each of the formulations produced opaque extrudates whenmelt extruded at 100° C. SEM revealed that crystalline itraconazole wasdispersed as discrete particles throughout the polymeric matrixfollowing extrusion for each composition.

DSC analysis of the compositions indicated that, at a loading of 10%(w/w), itraconazole it has a melting point of approximately 127° C.after melt extrusion with PEO at 100° C. Moreover, approximately thesame melting point for itraconazole was also observed when any one ofthe chosen polymers or surfactants was incorporated into the extrudedformulation.

Under the conditions evaluated, itraconazole is substantially insolublein PEO when extruded at 100° C. as confirmed by SEM and DSC. Inaddition, the solubility of itraconazole in PEO when melt extruded at100° C. was not influenced by the inclusion of HPMC, Poloxamer 407, PVA,or SLS to the formulation.

The ability of the carrier to provide a substantially stable releaseprofile after storage of a composition according to the invention wasdetermined by conducting dissolution profile assays for various controlsand sample. FIG. 7 depicts exemplary drug release profiles for thecomposition of Example 1. The first line (diamond markers) depicts therelease profile for danazol within one day of preparation of thecomposition. The second line (square markers) depicts the releaseprofile for danazol following 3 months storage in sealed containers at40° C. and 75% relative humidity. The drug release profile remainssubstantially the same.

The term “hot-melt extrusion” is used herein to describe a processwhereby an excipient blend is heated to a molten state and subsequentlyforced through an orifice where the extruded product is formed into itsfinal shape in which it is solidified upon cooling. The blend isconveyed through various heating zones typically by a screw mechanism.The screw or screws are rotated by a variable speed motor inside acylindrical barrel where only a small gap exists between the outsidediameter of the screw and the inside diameter of the barrel. In thisconformation, high shear is created at the barrel wall and between thescrew fights by which the various components of the powder blend arewell mixed and deaggregated. The hot-melt extrusion equipment istypically a single or twin-screw apparatus, but can be composed of morethan two screw elements. A typical hot-melt extrusion apparatus containsa mixing/conveying zone, a heating/melting zone, and a pumping zone insuccession up to the orifice. In the mixing/conveying zone, the powderblends are mixed and aggregates are reduced to primary particles by theshear force between the screw elements and the barrel. In theheating/melting zone, the temperature is at or above the melting pointor glass transition temperature of the thermal binder or binders in theblend such that the conveying solids become molten as they pass throughthe zone. A thermal binder in this context describes an inert excipient,typically a polymer, that is sufficiently solid at ambient temperature,but becomes molten or semi-liquid when exposed to elevated heat orpressure. The thermal binder acts as the matrix in which the active oractives and other functional ingredients are dispersed, or the adhesivewith which they are bound such that a continuous composite is formed atthe outlet orifice. Once in a molten state, the homogenized blend ispumped to the orifice through another heating zone that maintains themolten state of the blend. At the orifice, the molten blend can beformed into strands, cylinders or films. The extrudate that exits isthen solidified typically by an air-cooling cooling process. Oncesolidified, the extrudate may then be further processed to form pellets,spheres, fine powder, tablets, and the like. An example of a singlescrew apparatus similar to the description above is the RandcastleMicrotruder, model RCP-0750.

For the proposed invention, the active substance or substances includefine drug particles that are produced by a mechanical milling, a solventbased phase separation, or a rapid freezing process. These fineparticles will enter the feeding zone of the extruder as aggregatedparticles due to strong interparticle cohesive forces. These fineparticles will be deaggregated and dispersed in the carrier system bythe high shear forces that exist between the screw elements and thebarrel. Thus, the process serves as a means of reducing fine particleaggregates to primary particles such that the full benefit of particlesize reduction is realized.

Temperature is an important process variable to consider for theproposed invention. To maintain the integrity of the fine drugparticles, the blend is extruded at least ten degrees Celsius or morebelow the temperature at which the active substance dissolves into thecarrier at the extruded ratio. For example, itraconazole is solubilizedby PEO at approximately 127° C. in a nine to one ratio of PEO toitraconazole. Therefore, when extruding fine particles of itraconazolein a PEO carrier at a nine to one ratio, the greatest extrusiontemperature must be at most 117° C. For amorphous fine drug particles,this maximum extrusion temperature is the temperature at which thestabilizing excipients become labile to an extent that recrystallizationof the drug occurs. Therefore, it is important to formulate amorphousdrug particles to include such excipients as polymers with high glasstransition temperatures so that the maximum extrusion temperature is ina range above the softening temperatures of common thermal binders.Thus, the temperature at which the active compound dissolves into acarrier formulation or at which amorphous fine drug particles begin torecrystallize must be determined experimentally before deciding the mostappropriate extrusion conditions. This can be done by DSC analysis forvarying ratios of active particles to carrier and noting the temperatureof the thermal event associated with the drug, i.e. the endothermicevent for the melting point of crystalline drug and the exothermic eventfor the recrystallization of amorphous drug. When extruding compositionscontaining amorphous drug particles, the maximum extrusion temperaturemust be below the temperature of recrystallization, approximately 10° to20° C. When extruding compositions containing crystalline drugparticles, the maximum extrusion temperature must be at least 10° C.below the melting point.

It follows from the discussion above that for a carrier system to beviable with a particular form of fine drug particles it must be hot-meltextrudable at temperatures below the maximum extrusion temperature ofthe active. If the carrier system does not become molten at the highestprocessing temperatures, an acceptable extruded product will not beformed. Therefore, the most appropriate extrusion temperature is thatwhich makes the carrier system molten and is below the solubilizationand/or recrystallization temperature of the active particles.

Other process variables such as feed rate and screw speed are optimizedto provide adequate shear and mixing so that the fine drug particles aredeaggregated and well dispersed as primary particles in the matrix ofthe carrier. The effect of feed rate and screw speed on such dependentvariables as the level of shear and mixing inside the extruder dependsheavily on the design of the equipment and namely the screw elements.Generally, increasing the screw speed will increase the shear forcesbetween the screw element and the barrel wall, thereby allowing for morerigorous mixing and a greater extent of particle deagregation.Decreasing the feed rate (non-flood feeding) will generally allow formore complete mixing and particle deagregation due a reduction in theamount of material within the extruder. For the present invention, thereshould be sufficient shearing to deaggregate the fine drug particles andhomogenously disperse the resulting primary particles throughout thecarrier matrix. To determine adequate shearing, the extruded product canbe examined by SEM to observe a typical particle size and degree ofparticle separation. If unsatisfactory deagregation or dispersion isseen, the feed rate may be reduced and/or screw speed increased toincrease the vigor of the mixing. It may also be beneficial to reprocessthe material by hot-melt extrusion one or more times to achieve ahomogenous deaggregated dispersion.

Consideration should be given to the manner in which the components of aformulation are fed to the extruder. In some embodiment, all formulationcomponents are blended together to form a blended mixture before beingfed to the extruder. This can be done by any traditional mixing orblending technique. Alternatively, formulation components may be fedindividually if done simultaneously, and given that there is adequatemixing of the formulation components in the mixing/conveying zone of theextruder.

A desiccant can be used to aid in storing a formulation according to theinvention in order to help maintain a stable release profile. Suitabledesiccants include sodium sulfate, calcium sulfate, magnesium sulfate,sodium hydroxide, sodium bicarbonate, clay, vermiculite, paper,activated alumina, zeolite, calcium chloride, molecular sieve, oranhydrous chemicals. Accordingly, the method of invention forstabilizing the release profile of a film-coated dosage form cancomprise the step of including a desiccant in the container in which thedosage form is stored. In some cases a desiccant is needed if thecarrier materials of the drug are hygroscopic since moisture may affectthe physical stability of the primary crystalline or amorphousparticles.

The influence of storage time, temperature and relative humidity uponthe release profiles of composition made herein is depicted in FIG. 8.FIG. 8 compares, before and after storage, the release profiles ofdanazol dispersions made according to the proposed invention with anamorphous solid solution of danazol whereby amorphous drug particles areformed in-situ during hot-melt extrusion. Lines on FIG. 8 denoted bytriangular and diamond shaped markers represent the two formulationsprior to storage, both showing similar release profiles. Lines on FIG. 8denoted by square and x shaped markers show the dissolution profile ofthe two formulations after three month storage in sealed containers at40° C. and 75%. It can be seen that the dissolution rate of the danazoldispersion produced by in-situ formation of amorphous danazol particlesis significantly decreased after storage. This is the result ofagglomeration and recrystallization of amorphous danazol particles dueto the perturbations during storage. This decrease is not seen in thecase of the formulation produced according to the proposed inventionbecause fine drug particles of danazol are stabilized againstrecrystallization by formulation with a stabilizing excipient during theproduction of the particles. Additionally aggregation of fine danazolparticles is prevented by the stabilizing nature of the carrier system.Thus, the physical stability of the fine drug particles is maintainedand hence the dissolution profile is maintained unchanged with storage.

FIG. 9 depicts DSC thermograms obtained according to Example 3 ofPVP-stabilized amorphous ITZ particles (Example 9), extrudatescontaining PVP-stabilized amorphous ITZ (Example 10), a physical mixtureof crystalline ITZ with the excipient components of Examples 9 and 10,PVP K25, and bulk crystalline ITZ. The DSC thermograms indicate that thePVP-stabilized ITZ particles are substantially amorphous compared tobulk ITZ as seen by the complete absence of an endothermic event at 165°C. that is associated with the melting of crystalline ITZ. Thethermograms also demonstrate that the amorphous nature of thePVP-stabilized ITZ particles is maintained during the melt extrusionprocess as seen by the absence of an endothermic event at approximately160° C. as is seen with the physical mixture containing crystalline ITZ.This figure demonstrates that the amorphous nature of the PVP-stabilizedamorphous ITZ particles is not altered by hot hot-melt extrusion with anon-solubilizing carrier system when extrusion temperatures are wellbelow the T_(g) (glass transition temperature) the particle composite.

FIG. 10 depicts x-ray diffraction patterns obtained according to Example11 for poloxamer 407:PEO (7:3) placebo extrudate, a physical mixture ofcrystalline ITZ with the excipient components of Examples 9 and 10,extrudates containing PVP-stabilized amorphous ITZ (Example 10), bulkITZ, and PVP-stabilized amorphous ITZ (Example 9). The results show asubstantially amorphous content of drug for both Example 9 and Example10 when compared to the control bulk crystalline itraconazole sample andphysical mixture. The peaks noted with the red arrows are peaksassociated with crystalline ITZ as are seen with the bulk drug and thephysical mixture, yet not seen in Example 9 or 10. This figure serves assupplemental analysis to DSC in its demonstration that the amorphousnature of the PVP-stabilized amorphous ITZ particles is not altered byhot-melt extrusion with a non-solubilizing carrier system when extrusiontemperatures are sufficiently below the T_(g) the particle composite.

FIGS. 11a-11d depict SEM images obtained according to Example 2 forsamples prepared according to Example 9 (FIG. 11a ), a Poloxamer:PEO(7:3) placebo extrudate (FIG. 11b ), and samples prepared accordingExample 10 (FIGS. 11c and 11d ). From a comparison of the SEM images, itcan be seen that the PVP-stabilized amorphous ITZ particles are notmolten during hot-melt extrusion and are dispersed within the polymermatrix as discernable, individualized particles by the hot-meltextrusion process.

FIG. 12 depicts the results of a comparative dissolution test obtainedaccording to Example 12 for samples made according to Example 10,samples made according to Example 9, and bulk ITZ. The figuredemonstrates that the dissolution rate of ITZ is faster in the case ofthe extrudates than the amorphous particles alone with 90% drug releasein 10 minutes compared to 62%, respectively. Both the extrudates and theamorphous particles exhibited substantially faster dissolution ratesover the bulk ITZ as the bulk ITZ showed less than 1% dissolved in 10minutes. This figure demonstrates that hot-melt extrusion ofPVP-stabilized amorphous ITZ particles in a hydrophilic carrier improvesthe dissolution properties of the particles. This improvement is theresult of increased surface area and enhanced wettability of the drugparticles by deaggregation and dispersion of the particles into ahydrophilic carrier via the hot-melt extrusion process. The substantialimprovement of the extrudates and the amorphous particles alone over thebulk ITZ demonstrates the benefit of formulating ITZ in the amorphousstate for achieving rapid dissolution.

FIG. 13 depicts comparative dissolution profiles for samples madeaccording to Example 9 and samples made according to Example 10 beforeand after storage according to Example 4 at conditions of 40° C. and 75%relative humidity in aluminum induction sealed high density polyethylenebottles for a period of two weeks. The dissolution profile of thehot-melt extruded amorphous ITZ particles is stable on storage for 2weeks, whereas the dissolution profile of the amorphous particles aloneis unstable as it was substantially decreased on storage. This figuredemonstrates the effect that hot-melt extruding the amorphous ITZparticles in a stabilizing carrier system has upon dissolution profilestability. The stabilizing carrier system protects the drug particlesfrom ambient moisture absorption that would otherwise lead to particleaggregation and recrystallization of the amorphous drug. Theaforementioned effects of ambient moisture absorption are clearly seenwith the decrease in dissolution rate of the amorphous ITZ particlesafter 2 weeks storage.

FIG. 14 depicts DSC thermograms obtained according to Example 3 forsamples produced according to Example 13, samples produced according toExample 14, a physical mixture of crystalline CBM with the excipientcomponents of examples 13 and 14, and PVP K25. The DSC thermogramsindicate that the PVP-stabilized CBM particles are substantiallyamorphous as seen by the complete absence of the endothermic event at190° C. that is associated with the melting of crystalline CBM. Thethermograms also indicate that the morphology of PVP-stabilizedamorphous CBM particles was not altered by the hot-melt extrusionprocess as seen by the absence of the broad endothermic event in therange of 170 to 190° C. that is associated with the melting ofcrystalline CBM in the presence of the other excipients as seen with thephysical mixture. This figure therefore demonstrates that the morphologyof the PVP-stabilized amorphous CBM particles is not altered by hot-meltextrusion with a non-solubilizing carrier formulation when extrusiontemperature is sufficiently lower than the T_(g) of the particlecomposite.

FIG. 15 depicts x-ray diffraction patterns obtained according to Example11 for poloxamer 407:PEO (7:3) placebo extrudate, a physical mixture ofcrystalline CBM with the excipient components of Examples 13 and 14,samples produced according to Example 14, samples produced according toExample 13, and bulk CBM. The data indicate a substantially amorphouscontent of drug for both Example 13 and Example 14 when compared to thecontrol bulk crystalline itraconazole sample and physical mixture. Thepeaks noted with the arrows are peaks associated with crystalline CBM asare seen with the bulk drug and the physical mixture, yet not seen withthe sample of either Example 13 or Example 14. This figure serves assupplemental analysis to DSC in its demonstration that the amorphousnature of the PVP-stabilized amorphous CBM particles is not altered byhot-melt extrusion with a non-solubilizing carrier system when extrusiontemperatures are well below the T_(g) the particle composite.

FIG. 16 comparative dissolution profiles obtained according to Example12 for samples made according to Example 13 and samples made accordingto Example 14. The figure demonstrates that the dissolution rate of CBMis faster in the case of the extrudates than the amorphous particlesalone with 93% drug release in 10 minutes compared to 78%, respectively.This figure demonstrates that hot-melt extruding PVP-stabilizedamorphous CBM particles in a hydrophilic carrier improves thedissolution properties of the particles. This improvement is the resultof increased surface area and enhanced wettability of the drug particlesby deaggregation and dispersion of the particles into a hydrophiliccarrier via the hot-melt extrusion process.

FIG. 17 depicts comparative dissolution profiles for samples madeaccording to Example 13 and Example 14 in which the amount of CBM addedto each dissolution vessel (200 mg/900 ml) was several times greaterthan the equilibrium saturation solubility. This is in contrast to theprevious figure where the concentration of the drug in each dissolutionvessel (10 mg/900 ml) was below the equilibrium solubility. This figuredemonstrates that extrudates containing CBM amorphous particles reachhigher levels of supersaturation with a much more rapid dissolution ratethan the amorphous particles alone. Because of the increased amount ofmaterial in each dissolution vessel, the hydrophobic attraction of theamorphous CBM particles in the dissolution media that causes them toaggregate and which impedes dissolution was more pronounced. Thishydrophobic attraction is greatly reduced by hot-melt extruding the CBMamorphous particles in a hydrophilic carrier which renders the particlesmore wettable, and thus increases the rate and extent of dissolution.

FIG. 18 depicts comparative dissolution profiles for samples madeaccording to Example 13 and samples made according to Example 14 beforeand after storage according to Example 4 at conditions of 40° C. and 75%relative humidity in aluminum induction sealed high density polyethylenebottles for a period of two weeks. It can be seen in the figure that thedissolution profile of the hot-melt extruded amorphous CBM particles isstable following 2 weeks of storage, whereas the dissolution profile ofthe amorphous particles alone is unstable as it was substantiallydecreased on storage. This figure demonstrates the effect of hot-meltextruding the amorphous CBM particles in a stabilizing carrier systemthat protects them from ambient moisture absorption that leads toparticle aggregation and recrystallization of the amorphous drug. Theaforementioned effects of ambient moisture absorption are clearly seenby the decrease in dissolution rate of the amorphous CBM particles after2 weeks storage.

FIG. 19 depicts DSC thermograms obtained according to Example 3 forsamples produced according to Example 15, HPMC E3, samples producedaccording to Example 16, a physical mixture of crystalline KCZ with theexcipient components of Examples 15 and 16, and bulk ketoconazole. TheDSC thermograms indicate that the HPMC-stabilized KCZ particles aresubstantially amorphous compared to bulk ketoconazole as seen by thecomplete absence of the endothermic event at 151° C. associated with themelting of crystalline KCZ. The thermograms also indicate that themorphology of HPMC-stabilized amorphous KCZ particles was not altered bythe hot-melt extrusion process. This is evidenced by the absence of thebroad endothermic event with the peak value at 142° C. observed with thephysical mixture, which peak is associated with the melting ofcrystalline KCZ in the presence of the other excipients. This figuretherefore demonstrates that the morphology of the HPMC-stabilizedamorphous KCZ particles is not altered by hot-melt extrusion with anon-solubilizing carrier formulation when extrusion temperature issufficiently lower than the T_(g) of the particle composite.

FIGS. 20a-20b depict SEM images obtained according to Example 2 ofsamples prepared according to Example 17 (FIG. 20a ) and samplesprepared according Example 18 (FIG. 20b ). FIG. 20a depicts a largeaggregate of fine crystalline DNZ particles, with some of the smallerparticles having diameters near 100 nm. FIG. 20b depicts finecrystalline DNZ particles hot-melt extruded with a non-solubilizingpolymeric carrier. It can be seen from the figure that large aggregatesof fine crystalline DNZ particles are broken up and dispersed within thepolymeric matrix as discernable, individualized particles by thehot-melt extrusion process. Additionally, it can be seen that theindividual DNZ particles are not solubilized by the polymeric carrierduring hot-melt extrusion.

In view of the present disclosure, the invention provides apharmaceutical composition possessing a stabilized release profile, thecomposition comprising fine drug-containing particles dispersed in anonsolubilizing and stabilizing carrier, the pharmaceutical compositionhaving been prepared by a method comprising the step of: providing acharge of fine drug-containing particles of a therapeutic compound;

-   providing a charge of stabilizing and non-solubilizing hot-melt    extrudable carrier; and-   mixing and hot-melting extruding the charges to form the hot-melt    extruded pharmaceutical composition; wherein a substantial majority    of the fine drug particles are not agglomerated or aggregated during    the step of hot-melt extruding.

As used herein, the term “opaquant” is intended to mean a compound usedto render a composition opaque. May be used alone or in combination witha colorant. Such compounds include, by way of example and withoutlimitation, titanium dioxide and other materials known to one ofordinary skill in the art.

Some of the materials listed herein may be too brittle or may have Tgvalues that are generally too high rendering them too difficult toextrude. The glass transition temperature is reduced upon the additionof a plasticizer. As used herein, the glass transition temperature istaken to mean the temperature at which a solid material softens or melts(or the glass transition temperature (Tg) is the temperature at which apolymer changes during the heat cycle from a brittle substance (glass)to a rubbery mass). Such materials can be combined with one or moreplasticizers to render them thermoformable. Plasticizers, such as lowmolecular weight PEG, generally broaden the average molecular weight ofa polymer in which they are included thereby lowering its glasstransition temperature or softening point. Plasticizers also generallyreduce the viscosity of a polymer. It is possible the plasticizer willimpart some particularly advantageous physical properties to the film ofthe invention.

Plasticizers useful in the invention can include, by way of example andwithout limitation, low molecular weight polymers, oligomers,copolymers, oils, small organic molecules, low molecular weight polyolshaving aliphatic hydroxyls, ester-type plasticizers, glycol ethers,poly(propylene glycol), multi-block polymers, single block polymers, lowmolecular weight poly(ethylene glycol), citrate ester-type plasticizers,triacetin, propylene glycol and glycerin. Such plasticizers can alsoinclude ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol,styrene glycol, diethylene glycol, triethylene glycol, tetraethyleneglycol and other poly(ethylene glycol) compounds, monopropylene glycolmonoisopropyl ether, propylene glycol monoethyl ether, ethylene glycolmonoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate,ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate,acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate,tributyl citrate and allyl glycolate. All such plasticizers arecommercially available from sources such as Aldrich or Sigma ChemicalCo. It is also contemplated and within the scope of the invention, thata combination of plasticizers may be used in the present formulation.The PEG based plasticizers are available commercially or can be made bya variety of methods, such as disclosed in Poly(ethylene glycol)Chemistry: Biotechnical and Biomedical Applications (J. M. Harris, Ed.;Plenum Press, NY) the disclosure of which is hereby incorporated byreference.

Preservatives include compounds used to prevent the growth ofmicroorganisms. Suitable preservatives include, by way of example andwithout limitation, benzalkonium chloride, benzethonium chloride, benzylalcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethylalcohol, phenylmercuric nitrate and thimerosal and others known to thoseof ordinary skill in the art.

As used herein, the term “flavorant” is intended to mean a compound usedto impart a pleasant flavor and often odor to a pharmaceuticalpreparation. Exemplary flavoring agents or flavorants include syntheticflavor oils and flavoring aromatics and/or natural oils, extracts fromplants, leaves, flowers, fruits and so forth and combinations thereof.These may also include cinnamon oil, oil of wintergreen, peppermintoils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaveoil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.Other useful flavors include vanilla, citrus oil, including lemon,orange, grape, lime and grapefruit, and fruit essences, including apple,pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot andso forth. Flavors that have been found to be particularly useful includecommercially available orange, grape, cherry and bubble gum flavors andmixtures thereof. The amount of flavoring may depend on a number offactors, including the organoleptic effect desired. Flavors will bepresent in any amount as desired by those of ordinary skill in the art.Particularly preferred flavors are the grape and cherry flavors andcitrus flavors such as orange.

It should be understood, that compounds used in the art ofpharmaceutical formulation generally serve a variety of functions orpurposes. Thus, if a compound named herein is mentioned only once or isused to define more than one term herein, its purpose or function shouldnot be construed as being limited solely to that named purpose(s) orfunction(s).

The solid substrate of the invention will include an active agent whenincluded in a dosage form. Generally an effective amount of active agentis included. By the term “effective amount”, it is understood that, withrespect to, for example, pharmaceuticals, a therapeutically effectiveamount is contemplated. A therapeutically effective amount is the amountor quantity of drug that is sufficient to elicit the required or desiredtherapeutic response, or in other words, the amount that is sufficientto elicit an appreciable biological response when administered to apatient.

The active agent can be present in its free acid, free base orpharmaceutically acceptable salt form. As used herein, “pharmaceuticallyacceptable salts” refer to derivatives of the disclosed compoundswherein the active agent is modified by making acid or base saltsthereof. Examples of pharmaceutically acceptable salts include, but arenot limited to, mineral or organic acid salts of the drug. Thepharmaceutically acceptable salts include the conventional non-toxicsalts, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic,sulfamic, phosphoric, nitric and the like; and the salts prepared fromorganic acids such as amino acids, acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and other known to those ofordinary skill in the pharmaceutical sciences. Lists of suitable saltsare found in texts such as Remington's Pharmaceutical Sciences, 18th Ed.(Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, Pa., 1990);Remington: the Science and Practice of Pharmacy 19^(th) Ed. (Lippincott,Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3rdEd. (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc., 1999); thePharmaceutical Codex: Principles and Practice of Pharmaceutics 12^(th)Ed. (Walter Lund ed.; Pharmaceutical Press, London, 1994); The UnitedStates Pharmacopeia: The National Formulary (United States PharmacopeialConvention); and Goodman and Gilman's: the Pharmacological Basis ofTherapeutics (Louis S. Goodman and Lee E. Limbird, eds.; McGraw Hill,1992), the disclosures of which are hereby incorporated by reference.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, the terms “therapeutic compound”, “therapeutic agent”,“active agent” and “drug” are used interchangeably, unless otherwisespecified. The process of the invention can be used to preparecomposition and dosage forms comprising essentially any one or moreactive agents. Active agents include physiological substances orpharmacological active substances that produce a systemic or localizedeffect or effects on animals and human beings. Active agents alsoinclude pesticides, herbicides, insecticides, antioxidants, plant growthinstigators, sterilization agents, catalysts, chemical reagents, foodproducts, nutrients, cosmetics, vitamins, minerals, dietary supplements,sterility inhibitors, fertility instigators, microorganisms, flavoringagents, sweeteners, cleansing agents and other such compounds forpharmaceutical, veterinary, horticultural, household, food, culinary,agricultural, cosmetic, industrial, cleansing, confectionery andflavoring applications. The active agent can be present in its neutral,ionic, salt, basic, acidic, natural, synthetic, diastereomeric,isomeric, enantiomerically pure, racemic, hydrate, chelate, derivative,analog, or other common form.

Further therapeutic compounds which can be formulated into the presentcomposition also include antibacterial substance, antihistamine(histamine receptor inhibitor), decongestant, anti-inflammatory agent,antiparasitic agent, antiviral agent, local anesthetic, antifungalagent, amoebicidal agent, trichomonocidal agent, analgesic agent,antiarthritic agent, antiasthmatic agent, anticoagulant agent,anticonvulsant agent, antidepressant agent, antidiabetic agent,antineoplastic agent, antipsychotic agent, neuroleptic agent,antihypertensive agent, muscle relaxant, depressant agent, hypnoticagent, sedative agent, psychic energizer, tranquilizer, antiparkinsonagent, muscle contractant, anti-microbial agent, antimalarial agent,hormonal agent, contraceptive agent, sympathomimetic agent, diureticagent, hypoglycemic agent, ophthalmic agent, anti-hypercholesterolemiaagent, anti-hypocholesterolemia agent, electrolyte, diagnostic agent,cardiovascular drug, vitamin, nutrient, other type of therapeuticcompound known to those of ordinary skill in the pharmaceuticalsciences, and combinations thereof.

Representative active agents include nutrients and nutritional agents,hematological agents, endocrine and metabolic agents, cardiovascularagents, renal and genitourinary agents, respiratory agents, centralnervous system agents, gastrointestinal agents, anti-infective agents,biologic and immunological agents, dermatological agents, ophthalmicagents, antineoplastic agents, and diagnostic agents. Exemplarynutrients and nutritional agents include as minerals, trace elements,amino acids, lipotropic agents, enzymes and chelating agents. Exemplaryhematological agents include hematopoietic agents, antiplatelet agents,anticoagulants, coumarin and indandione derivatives, coagulants,thrombolytic agents, antisickling agents, hemorrheologic agents,antihemophilic agents, hemostatics, plasma expanders and hemin.Exemplary endocrine and metabolic agents include sex hormones,uterine-active agents, bisphosphonates, antidiabetic agents, glucoseelevating agents, adrenocortical steroids, parathyroid hormone, thyroiddrugs, growth hormones, posterior pituitary hormones, octreotideacetate, imiglucerase, calcitonin-salmon, sodium phenylbutyrate, betaineanhydrous, cysteamine bitartrate, sodium benzoate and sodiumphenylacetate, bromocriptine mesylate, cabergoline, agents for gout, andantidotes.

Exemplary cardiovascular agents include nootropic agents, antiarrhythmicagents, calcium channel blocking agents, vasodilators,antiadrenergics/sympatholytics, renin angiotensin system antagonists,antihypertensive combinations, agents for pheochromocytoma, agents forhypertensive emergencies, antihyperlipidemic agents, antihyperlipidemiccombination products, vasopressors used in shock, potassium removingresins, edetate disodium, cardioplegic solutions, agents for patentductus arteriosus, and sclerosing agents. Exemplary renal andgenitourinary agents include interstitial cystitis agents, cellulosesodium phosphate, anti-impotence agents, acetohydroxamic acid (aha),genitourinary irrigants, cystine-depleting agents, urinary alkalinizers,urinary acidifiers, anticholinergics, urinary cholinergics, polymericphosphate binders, vaginal preparations, and diuretics. Exemplaryrespiratory agents include bronchodilators, leukotriene receptorantagonists, leukotriene formation inhibitors, nasal decongestants,respiratory enzymes, lung surfactants, antihistamines, nonnarcoticantitussives, and expectorants. Exemplary central nervous system agentsinclude CNS stimulants, narcotic agonist analgesics, narcoticagonist-antagonist analgesics, central analgesics, acetaminophen,salicylates, nonnarcotic analgesics, nonsteroidal anti-inflammatoryagents, agents for migraine, antiemetic/antivertigo agents, antianxietyagents, antidepressants, antipsychotic agents, cholinesteraseinhibitors, nonbarbiturate sedatives and hypnotics, nonprescriptionsleep aids, barbiturate sedatives and hypnotics, general anesthetics,anticonvulsants, muscle relaxants, antiparkinson agents, adenosinephosphate, cholinergic muscle stimulants, disulfuram, smokingdeterrents, riluzole, hyaluronic acid derivatives, and botulinum toxins.Exemplary gastrointestinal agents including H pylori agents, histamineH2 antagonists, proton pump inhibitors, sucralfate, prostaglandins,antacids, gastrointestinal anticholinergics/antispasmodics, mesalamine,olsalazine sodium, balsalazide disodium, sulfasalazine, celecoxib,infliximab, esomeprazole, famotidine, lansoprazole, omeprazole,pantoprazole, rabeprazole, tegaserod maleate, laxatives, antidiarrheals,antiflatulents, lipase inhibitors, GI stimulants, digestive enzymes,gastric acidifiers, hydrocholeretics, gallstone solubilizing agents,mouth and throat products, systemic deodorizers, and anorectalpreparations. Exemplary anti-infective agents including penicillins,such as amoxicilin, cephalosporins and related antibiotics, carbapenem,monobactams, chloramphenicol, quinolones, fluoroquinolones,tetracyclines, macrolides, such as azithromycin, clarithromycin, and thelike, spectinomycin, streptogramins, vancomycin, oxalodinones,lincosamides, oral and parenteral aminoglycosides, colistimethatesodium, polymyxin B sulfate, bacitracin, metronidazole, sulfonamides,nitrofurans, methenamines, folate antagonists, antifungal agents, suchas fluconazole, voriconazole, and the like, antimalarial preparations,antituberculosis agents, amebicides, antiviral agents, antiretroviralagents, leprostatics, antiprotozoals, anthelmintics, and CDCanti-infective agents. Exemplary biologic and immunological agentsincluding immune globulins, monoclonal antibody agents, antivenins,agents for active immunization, allergenic extracts, immunologic agents,and antirheumatic agents. Exemplary antineoplastic agents includealkylating agents, antimetabolites, antimitotic agents,epipodophyllotoxins, antibiotics, hormones, enzymes,radiopharmaceuticals, platinum coordination complex, anthracenedione,substituted ureas, methylhydrazine derivatives, imidazotetrazinederivatives, cytoprotective agents, DNA topoisomerase inhibitors,biological response modifiers, retinoids, rexinoids, monoclonalantibodies, protein-tyrosine kinase inhibitors, porfimer sodium,mitotane (o, p′-ddd), and arsenic trioxide. Exemplary diagnostic agentsinclude in vivo diagnostic aids, in vivo diagnostic biologicals, andradiopaque agents.

Representative antibacterial substances are beta-lactam antibiotics,tetracyclines, chloramphenicol, neomycin, gramicidin, bacitracin,sulfonamides, aminoglycoside antibiotics, tobramycin, nitrofurazone,nalidixic acid, penicillin, tetracycline, oxytetracycline,chlorotetracycline, erythromycin, cephalosporins and analogs and theantimicrobial combination of fludalanine/pentizidone. Otherrepresentative antibacterial agents include of the poorly water-solublepyrridone-carboxylic acid type such as benofloxacin, nalidixic acid,enoxacin, ofloxacin, amifloxacin, flumequine, tosfloxacin, piromidicacid, pipemidic acid, miloxacin, oxolinic acid, cinoxacin, norfloxacin,ciprofloxacin, pefloxacin, lomefloxacin, enrofloxacin, danofloxacin,binfloxacin, sarafloxacin, ibafloxacin, difloxacin and salts thereof.

Representative antiparasitic compounds are ivermectin, bephenium,hydroxynaphthoate, praziquantel, nifurtimox, benznidasol, dichlorophenand dapsone. Representative anti-malarial compounds are4-aminoquinolines, 8-aminoquinolines and pyrimethamine.

Representative antiviral compounds are protease inhibitors,neuramidinase inhibitors, commercially available compounds, acyclovirand interferon.

Representative anti-inflammatory drugs include specific or selectiveCOX-2 receptor inhibitors, rofecoxib, celecoxib, etodolac, flurbiprofen,ibuprofen, ketoprofen, ketorolac, nabumetone, piroxicam, suprofen,tolmetin, zileuton, steroids, cyclooxygenase inhibitors, cortisone,hydrocortisone, betamethasone, dexamethasone, fluocortolone,prednisolone, phenylbutazone, triamcinolone, sulindac, indomethacin,salicylamide, naproxen, colchicine, fenoprofen, diclofenac, indoprofen,dexamethasone, allopurinol, oxyphenbutazone, probenecid and sodiumsalicylamide.

Representative analgesic drugs are diflunisal, aspirin, ibuprofen,profen-type compounds, morphine, codeine, levorphanol, hydromorphone,oxymorphone, oxycodone, hydrocodone, naloxene, levallorphan, etorphine,fentanyl, bremazocine, meperidine, nalorphine, tramadol, andacetaminophen.

Representative antihistamines and decongestants are acrivastine,astemizole, norastemizol, brompheniramine, cetirizine, clemastine,diphenhydramine, ebastine, famotidine, fexofenadine, meclizine,nizatidine, perilamine, promethazine, ranitidine, terfenadine,chlorpheniramine, cimetidine, tetrahydrozoline, tripolidine, loratadine,desloratadine, antazoline, and pseudoephedrine.

Representative antiasthma drugs are theophylline, ephedrine,beclomethasone dipropionate and epinephrine.

Representative anticoagulants are heparin, bishydroxycoumarin, andwarfarin.

Representative psychic energizers are isocoboxazid, nialamide,phenelzine, imipramine, tranycypromine, and parglyene.

Representative anticonvulsants are clonazepam, phenobarbital,mephobarbital, primidone, enitabas, diphenylhydantion, ethltion,pheneturide, ethosuximide, diazepam, phenytoin carbamazepine,lamotrigine, lorazepam, levetiracetam, oxcarbazepine, topiramate,valproic acid, chlorazepate, gabapentin, felbamate, tiagabine andzonisamide.

Representative antidepressants are amitriptyline, chlordiazepoxideperphenazine, protriptyline, imipramine, doxepin, venlafaxine,o-desmethyl venlafaxine, citalopram, escitalopram, bupropion,clomipramine, desipramine, nefazodone, fluoxetine, fluvoxamine,maprotiline, mirtazapine, nortriptyline, paroxetine, phenelzine,tranylcypromine, sertraline, trazodone, trimipramine, and amoxapine.

Representative antidiabetics are sulphonylureas, such as tolbutamide,chlorpropamide, tolazamide, acetohexamide, glibenclamide, gliclazide,1-butyl-3-metanilylurea, carbutamide, glibonuride, glipizide, glyburide,gliquidone, glisoxepid, glybuthiazole, glibuzole, glyhexamide,glymidine, glypinamide, phenbutamide, and tolcyclamide;thiazolidinediones (glitazones), such as rosiglitazone, pioglitazone,and troglitazone; biguanidines, such as metformin; and otherantidiabetic agents, such as nateglinide, repaglinide, insulin,somatostatin and its analogs, chlorpropamide, isophane insulin,protamine zinc insulin suspension, globin zinc insulin, and extendedinsulin zinc suspension.

Representative antineoplastics are chlorambucil, cyclophosphamide,triethylenemelamine, thiotepa, hexamethyl-melamine, busulfan,carmustine, lomustine, dacarbazine, arabinoside cytosine,mercaptopurine, azathiprine, vincristine, vinblastine, taxol, etoposide,actinomycin D, daunorubicin, doxorubicin, bleomycin, mitomycin;cisplatin; hydroxyurea, procarbazine, aminoglutethimide, tamoxifen,adriamycin, fluorouracil, methotrexate, mechlorethamine, uracil mustard,5-fluorouracil, 6-6-thioguanine and procarbazine asparaginase.

Representative steroidal drugs are prednisone, prednisolone, cortisone,cortisol and triamcinolone; androgenic steroids such as methyltesterone,and fluoxmesterone; estrogenic steroids such as 17β-estradiol,α-estradiol, estriol, α-estradiol 3 benzoate, and17-ethynylestradiol-3-methyl ether; progestational steriods such asprogesterone, 19-nor-pregn-4-ene-3,20-dione,17-hydroxy-19-nor-17-α-pregn-5(10)-ene-20-yn-3-one,17α-ethynyl-17-hydroxy-5 (10)-estren-3-one, and 9β,10α-pregna-4,6-diene-3,20-dione.

Representative estrogen antagonist-agonist drugs are clomiphene citrateand raloxifene HCl.

Representative antipsychotics are prochlorperazine, lithium carbonate,lithium citrate, thioridazine, molindone, fluphenazine, trifluoperazine,perphenazine, amitriptyline, trifluopromazine, chlorpromazine,clozapine, haloperidol, loxapine, mesoridazine, olanzapine, quetiapine,ziprasidone, risperidone, pimozide, mesoridazine besylate,chlorprothixene, and thiothixene.

Representative hypnotics and sedatives are pentobarbital sodium,phenobarbital, secobarbital, thiopental, heterocyclic hypnotics,dioxopiperidines, imidazopyridines, such as zolpidem tartrate,glutarimides, diethylisovaleramide, α-bromoisovaleryl urea, urethanes,disulfanes.

Representative antihypertensives are nifedipine, verapamil, diltiazem,felodipine, amlodipine, isradipine, nicardipine, nisoldipine,nimodipine, bepridil, enalapril, captopril, lisinopril, benazepril,enalaprilat, espirapril, fosinopril, moexipril, quinapril, ramipril,perindopril, trandolapril, furosemide, bumetanide, ethacrynic acid,torsemide, muzolimide, azosemide, piretanide, tripamide,hydrochlorothiazide, chlorthalidone, indapamide, metozalone,cyclopenthiazide, xipamide, mefruside, dorzolamide, acetazolamide,methazolamide, ethoxzolamide, cyclothiazide, clopamide,dichlorphenamide, hydroflumethiazide, trichlormethiazide, polythiazide,benzothiazide, spironolactone, methyldopa, hydralazine, clonidine,chlorothiazide, deserpidine, timolol, propranolol, metoprolol, pindolol,acebutolol, prazosin hydrochloride, methyl dopa(L-β-3,4-dihydroxyphenylalanine), pivaloyloxyethyl ester of α-methyldopahydrochloride dihydrate, candesartan cilexetil, eprosartan mesylate,losartan potassium, olmersartan medoxomil, telmisartan, valsartan, andreserpine.

Representative tranquilizers are chloropromazine, promazine,fluphenazine, reserpine, deserpidine, meprobamate, and benezodiazepines(anxyiolitic, sedatives, and hypnotics) such as alprazolam,chlordiazepoxide, diazepam, lorazepam, oxazepam, temazepam, andtriazolam.

Representative anti-spasmodics and muscle contractants are atropine,scopolamine, methscopolamine, oxyphenonium, papaverine, andprostaglandins such as PGE1 PGE2 PGF_(1α) PGF_(2α) and PGA.

Representative local anesthetics are benzocaine, procaine, lidocaine,maepaine, piperocaine, tetracaine and dibucaine.

Representative muscle relaxants are alcuronium, alosetron,aminophylline, baclofen, carisoprodol, chlorphenesin, chlorphenesincarbamate, chlorzoxazone, chlormezanone, dantrolene, decamethonium,dyphylline, eperisione, ethaverine, gallamine triethiodide,hexafluorenium, metaxalone, metocurine iodide, orphenadrine,pancuronium, papaverine, pipecuronium, theophylline, tizanidine,tolperisone, tubocurarine, vecuronium, idrocilamide, ligustilide,cnidilide, senkyunolide, succinylcholine-chloride, danbrolene,cyclobenzaprine, methocarbamol, diazepam, mephenesin, methocarbomal,trihexylphenidyl, pridinol (pridinolum), and biperiden.

Representative anti-Parkinson agents are carbidopa, levodopa,ropinirole, pergolide mesylate, rasagiline, pramipexole, entacapone,benzacide, bromocriptine, selegiline, amantadine, trihexylphenidyl,biperiden, pridinol mesylate, and tolcapone.

Representative anti-Dementia and anti-Alzheimer disease agents arememantine, donepexil, galantamine, rivastigmine, and tacrine

Representative sympathomimetic drugs are albuterol, epinephrine,amphetamine ephedrine and norepinephrine.

Representative cardiovascular drugs are procainamide, procainamidehydrochloride, amyl nitrite, nitroglycerin, dipyredamole, sodium nitrateand mannitol nitrate.

Representative diuretics are chlorothiazide, acetazolamide,methazolamide, triamterene, furosemide, indapamide, and flumethiazide.

Representative n-blockers are caravedilol, pindolol, propranolol,practolol, metoprolol, esmolol, oxprenolol, timolol, atenolol,alprenolol, and acebutolol.

Representative phosphodiesterase inhibitors are vardenafil HCl andsildenafil citrate.

Representative antilipemic agents are atorvastatin, cerivastatin,clofibrate, fluvastatin, gemfibrozil, lovastatin, mevinolinic acid,niacin, pravastatin, and simvastatin.

Representative antigout drugs are colchicine, allopurinol, probenecid,sulfinpyrazone, and benzbromadone.

Representative nutritional agents are ascorbic acid, niacin,nicotinamide, folic acid, choline biotin, panthothenic acid, and vitaminB₁₂, essential amino acids; essential fats.

Representative electrolytes are calcium gluconate, calcium lactate,potassium chloride, potassium sulfate, sodium chloride, potassiumfluoride, ferrous lactate, ferrous gluconate, ferrous sulfate, ferrousfumurate and sodium lactate.

Representative drugs that act on α-adrenergic receptors are clonidinehydrochloride, prazosin, tamsulosin, terazosin, and doxazosin.

Representative mild CNS stimulants are caffeine, modafinil, andmethylphenidate hydrochloride.

The formulation of the invention can also be used with unclassifiedtherapeutic agents such as clopidrogel, which is indicated for thereduction of atherosclerotic events (myocardial infarction, stroke, andvascular death) in patients with atherosclerosis documented by recentstroke, recent myocardial infarction, or established peripheral arterialdisease.

The active agents (drugs) listed herein should not be consideredexhaustive and is merely exemplary of the many embodiments consideredwithin the scope of the invention. Many other active agents can beadministered with the formulation of the present invention. Suitabledrugs are selected from the list of drugs included herein as well asfrom any other drugs accepted by the U.S.F.D.A. or other similarlyrecognized authority in Canada (Health Canada), Mexico (MexicoDepartment of Health), Europe (European Medicines Agency (EMEA)), SouthAmerica (in particular in Argentina (Administración Nacional deMedicamentos, Alimentos y Tecnología Medica (ANMAT) and Brazil(Ministério da Sande)), Australia (Department of Health and Ageing),Africa (in particular in South Africa (Department of Health) and Zimbawe(Ministry of Health and Child Welfare),) or Asia (in particular Japan(Ministry of Health, Labour and Welfare), Taiwan (Executive YuansDepartment of Health), and China (Ministry of Health People's Republicof China)) as being suitable for administration to humans or animals.Preferred embodiments of the invention include those wherein the activesubstance is pharmacologically or biologically active or wherein theenvironment of use is the GI tract of a mammal.

The amount of therapeutic compound incorporated in each dosage form willbe at least one or more unit doses and can be selected according toknown principles of pharmacy. An effective amount of therapeuticcompound is specifically contemplated. By the term “effective amount”,it is understood that, with respect to, for example, pharmaceuticals, apharmaceutically effective amount is contemplated. A pharmaceuticallyeffective amount is the amount or quantity of a drug or pharmaceuticallyactive substance which is sufficient to elicit the required or desiredtherapeutic response, or in other words, the amount which is sufficientto elicit an appreciable biological response when administered to apatient. The appreciable biological response may occur as a result ofadministration of single or multiple unit doses of an active substance.A dosage form according to the invention that comprises two or moreactive agents can include subtherapeutic amounts of one or more of thoseactive agents such that an improved, additive or synergistic clinicalbenefit is provided by the dosage form. By “subtherapeutic amount” ismeant an amount less than that typically recognized as being therapeuticon its own in a subject to which the dosage form is administered.Therefore, a dosage form can comprise a subtherapeutic amount of a firstdrug and a therapeutic amount of a second drug. Alternatively, a dosageform can comprise a subtherapeutic amount of a first drug and asubtherapeutic amount of a second drug.

The term “unit dose” is used herein to mean a dosage form containing aquantity of the therapeutic compound, said quantity being such that oneor more predetermined units may be provided as a single therapeuticadministration.

In view of the above description and the examples below, one of ordinaryskill in the art will be able to practice the invention as claimedwithout undue experimentation. The foregoing will be better understoodwith reference to the following examples that detail certain proceduresfor the preparation of formulations according to the present invention.All references made to these examples are for the purposes ofillustration. The following examples should not be consideredexhaustive, but merely illustrative of only a few of the manyembodiments contemplated by the present invention.

Example 1

The following process was used to prepare a hot-melt extrudedcomposition according to the invention. The following ingredients in theamounts indicated were used in preparing hot-melt extruded control andsample compositions containing itraconazole (ITZ) as the active agent.The amounts are indicates in parts by weight.

Poloxamer No. ITZ PEO HPMC PVA SLS 407 1 0 10 0 0 0 0 2 1 9 0 0 0 0 3 09 1 0 0 0 4 1 8 1 0 0 0 5 0 9 0 1 0 0 6 1 8 0 1 0 0 7 0 9 0 0 1 0 8 1 80 0 1 0 9 0 9 0 0 0 1 10 1 8 0 0 0 1

A Randcastle Microtruder RCP-0750 hot-melt extruder equipped with a 6 mmround die was operated at 15 RPM, 0.2-0.3 Drive Amps with an ExtrusionTemperature of 100° C. to prepare the composition. All powders wereblended in a v-shell blender prior to extrusion. Temperature zones wereset as follows: zone 1: 90° C., zone 2: 95° C., zone 3: 100° C., dietemperature 100° C. The powder blend was placed in a hopper that islocated at the head of a vertical screw such that the material is floodfed by gravity. The residence time of the material in the extruder wasapproximately three minutes. The extrudate was sheared intoapproximately one foot sections after exiting the die and placed on analuminum sheets and allowed to cool at ambient conditions.

Following preparation, the compositions can be analyzed by scanningelectron microscopy (SEM), differential scanning calorimetry (DSC),visual inspection, dissolution assays and other suitable methods ofanalysis.

Example 2

The fine drug-containing particles and compositions containing them wereanalyzed by scanning electron microscopy using a Hitachi S-4500 scanningelectron microscope. Samples were coated with Au/Pd and an acceleratingvoltage of 5 kV was used.

Example 3

Changes in the degree of crystallization of the fine drug-containingparticles, either neat or dispersed within a hot-melt extrudedcomposition, were determined and quantified by differential scanningcalorimetry. A TA Instruments Model 2920 calorimeter was used to conductthe analyses. The calorimeter was operated using the followingparameters:

Nitrogen Purge Flow Rate: 150 ml/min

Sample Pan: Aluminum (Closed)

Sample Weight: 10-15 mg

Heating Rate: 10° C./min

Range: 20-200° C.

The thermograms obtained from the DSC were analyzed using the TAUniversal Analysis Software in which peak minimums are determined bylinear baseline method with manually selected limits.

Example 4

The hot-melt extruded compositions were exposed to a variety ofdifferent storage conditions prior to determining their releaseprofiles. Samples were stored in sealed containers. Depending upon theconditions being evaluated, the closed containers might include adesiccant such as a silica gel mini-pack (Poly Lam Production Corp.).The containers were filled with hot-melt extruded compositions in anopen air environment and then sealed without purging the containersprior to sealing. The containers were then stored as desired under avariety of conditions:

Condition A: 25° C. and 60% RH

Condition B: 40° C. and 0% RH

Condition C: 40° C. and 75% RH

Example 5

Formulation:

Micronized Cyclosporine (mean particle diameter 2 microns): 15%

Ethylcellulose: 40%

Polyox 200M: 15%

LHPC: 8%

Lactose 16%

Xylitol: 5%

Vitamin E: 1%

A Randcastle Microtruder RCP-0750 hot-melt extruder equipped with a 6 mmround die was operated at 15 RPM, 0.2-0.3 Drive Amps with an ExtrusionTemperature of 100° C. to prepare the composition. All powders wereblended in a v-shell blender prior to extrusion. Temperature zones wereset as follows: zone 1: 90° C., zone 2: 95° C., zone 3: 100° C., dietemperature 100° C. The powder blend was placed in a hopper that islocated at the head of a vertical screw such that the material is floodfed by gravity. The residence time of the material in the extruder wasapproximately three minutes. The extrudate was sheared intoapproximately one foot sections after exiting the die and placed on analuminum sheets and allowed to cool at ambient conditions.

Example 6

The following procedure is used for the preparation of danazolnanoparticles using “spray freezing into liquid” technology.

Danazol (0.2% w/v) and PVP K15 (0.2% w/v) were dissolved in acetonitrile(500 ml). Aliquots of the solution (75 ml) were loaded into ahigh-pressure solution cell and atomized beneath the liquid nitrogensurface at 50 ml/min constant flow using a model 100DX ISCO syringe pump(ISCO, Inc., Lincoln, Nebr.) through a 127 μm I.D. polyetherether ketone(PEEK) tubing nozzle. The PEEK tubing acted as an insulating nozzle thatprevented freezing within the nozzle orifice. The resultant frozenmicroparticles were collected and dried by a VirTis Advantage TrayLyophilizer (VirTis Inc., Gardiner, N.Y.). The resulting product is afine powder of aggregated nanoparticles of amorphous danazol complexedwith PVP-K15 in a one to one ratio.

Example 7

The following procedure is used for the preparation of danazolnanoparticles using “evaporative precipitation into aqueous solution”(EPAS) technology.

Danazol (2% w/v) and PVP K-15 (1% w/v) were dissolved in 200 ml ofdichloromethane. This solution was pumped via an HPLC pump at 2 ml/minthrough a heat exchange coil set at 80° C. After heating, the solutionwas sprayed through a fine elliptical conical nozzle at 5000 psiconstant pressure into a heated water bath (80° C.) containing PVP K-15(1% w/v) dissolved in 200 ml deionized water. The resultant dispersionwas quenched frozen by injecting it into liquid nitrogen and lyophilizedas in example 6. The resulting product is a fine powder of aggregatednanoparticles of amorphous danazol complexed with PVP-K15 in a two toone ratio.

Example 8

Hot-Melt Extrusion of Amorphous Fine Drug Particles of Danazol

Because the fine drug particles described in examples 6 and 7 containPVP-K15 as a major constituent, which has a glass transition temperatureof 150° C., the nanoparticle complex will maintain its integrity andthereby its amorphous state if extruded at temperatures of 100° C. orbelow. The following is an example of a hot melt extrusion formulationand process by which a homogenous extrudate of individualized andstabilized danazol/PVP K-15 nanoparticles can be produced.

Formulation:

Danazol nanoparticles according to examples 6 or 7: 35%

PEO 200M: 50%

HPMC E15: 15%

Process:

A Randcastle Microtruder RCP-0750 hot-melt extruder equipped with a 6 mmround die was operated at 15 RPM, 0.2-0.3 Drive Amps with an ExtrusionTemperature of 90° C. to prepare the composition. All powders wereblended in a v-shell blender prior to extrusion. Temperature zones wereset as follows: zone 1: 80° C., zone 2: 85° C., zone 3: 90° C., dietemperature 90° C. The powder blend was placed in a hopper that islocated at the head of a vertical screw such that the material is floodfed by gravity. The residence time of the material in the extruder wasapproximately three minutes. The extrudate was sheared intoapproximately one-foot sections after exiting the die and placed on analuminum sheets and allowed to cool at ambient conditions.

Example 9

The following procedure is used for the preparation of PVP-stabilizedamorphous itraconazole particles using an evaporative co-precipitationtechnology.

Formulation:

Component Quantity Itraconazole (ITZ) 50% Polyvinylpyrrolidone 50% (PVP;grade K25) Dichloromethane 5 mL/g solids

Solid components listed the table above were dissolved into the organicsolvent with the use of an Aquasonic Model 150T ultrasonicator. Thesolvent was then completely evaporated in a vacuum chamber at atemperature of 40° C. and pressure of 500 mTorr to yield a dry solidproduct. The solid product was subsequently triturated in a glass mortarand pestle for 2 to 5 minutes to yield PVP-stabilized amorphousitraconazole particles with individual particle diameters ranging from 2to 100 μm.

Example 10

Hot-Melt Extrusion of Amorphous Fine Drug Particles of Itraconazole

Because the fine drug particles described in Example 9 contain PVP-K25as a major constituent, which has a glass transition temperature ofapproximately 150° C., the amorphous microparticle complex will maintainits integrity and thereby its amorphous state if extruded attemperatures of approximately 100° C. or below. The following is anexample of a hot-melt extrusion formulation and process by which ahomogenous extrudate of individualized and stabilizeditraconazole/PVP-K25 amorphous microparticles can be produced.

Formulation:

Component Quantity Itraconazole/PVP-K25 amorphous 50% microparticles(Example 9) Poloxamer 407 35% Sentry Poloyox WSR N80 (PEO) 15%

Process:

A Randcastle Microtruder RCP-0750 hot-melt extruder equipped with a 4 mmround die was operated at 20 RPM, 0.1-0.2 drive amps, and at a melttemperature of 60° C. to prepare the composition. All powders wereblended in a v-shell blender prior to extrusion. Temperature zones wereset as follows: zone 1: 40° C., zone 2: 60° C., zone 3: 60° C., dietemperature 60° C. The powder blend was placed in a hopper that islocated at the head of a vertical screw such that the material is floodfed by gravity. The residence time of the material in the extruder wasapproximately two minutes. The extrudate was sheared into approximatelyone foot sections after exiting the die and placed on aluminum sheetsand allowed to cool at ambient conditions. After cooling, the extrudateswere milled with a ceramic mortar and pestle and passed through a 250 μmsieve.

Example 11

Changes in the degree of crystallization of the fine drug-containingparticles, either neat or dispersed within a hot-melt extrudedcomposition, were determined by x-ray diffraction. A model 1710 x-raydiffractometer (Philips Electronic Instruments, Inc., Mahwah, N.J.)using a Cu2α monochromated x-ray source was used to conduct the analyseswith a 0.05°/2θ step size and a 2 second dwell time. The output data wasplotted as peak intensity versus 2θ angle, and the plots werequalitatively analyzed for the presence of peaks indicatingcrystallinity of the drug substance.

Example 12

The dissolution profiles of the fine-drug containing particles, eitherneat or dispersed within a hot-melt extruded composition, weredetermined using a USP 27 Type II paddle apparatus model VK7000 (VarianInc., Palo Alto, Calif.) at 37° C. and 50 rpm paddle speed.

The dissolution media was 900 ml of 0.1 N HCl, and was de-aerated withhelium for approximately 15 minutes before each dissolution test. In allcases where not otherwise specified, the equivalent to 10 mg of theactive ingredient was added to each dissolution vessel.

Example 13

The following procedure is used for the preparation of PVP-stabilizedamorphous carbamazepine particles using an evaporative co-precipitationtechnology.

Formulation:

Component Quantity Carbamazepine (CBM) 50% Polyvinylpyrrolidone 50%(PVP; grade K30) Dichloromethane 5 mL/g solids

Procedure:

Solid components listed the table above were dissolved into the organicsolvent with the use of an Aquasonic Model 150T ultrasonicator. Thesolvent was then completely evaporated in a vacuum chamber at atemperature of 40° C. and pressure of 500 mTorr to yield a dry solidproduct. The solid product was subsequently triturated in a glass mortarand pestle for 2 to 5 minutes to yield PVP-stabilized amorphouscarbamazepine particles with individual particle diameters ranging from2 to 100 μm.

Example 14

Hot-Melt Extrusion of Amorphous Fine Drug Particles of Carbamazepine

Because the fine drug particles described in Example 13 contain PVP-K30as a major constituent, which has a glass transition temperature ofapproximately 150° C., the amorphous microparticle complex will maintainits integrity and thereby its amorphous state if extruded attemperatures of approximately 100° C. or below. The following is anexample of a hot-melt extrusion formulation and process by which ahomogenous extrudate of individualized and stabilizedcarvamazepine/PVP-K30 amorphous microparticles can be produced.

Formulation:

Component Quantity Carbamazepine/PVP-K30 amorphous 50% microparticles(Example 13) Poloxamer 407 35% Sentry Poloyox WSR N80 (PEO) 15%

Process:

A Randcastle Microtruder RCP-0750 hot-melt extruder equipped with a 4 mmround die was operated at 20 RPM, 0.1-0.2 Drive Amps at a melttemperature of 60° C. to prepare the composition. All powders wereblended in a v-shell blender prior to extrusion. Temperature zones wereset as follows: zone 1: 40° C., zone 2: 60° C., zone 3: 60° C., dietemperature 60° C. The powder blend was placed in a hopper that islocated at the head of a vertical screw such that the material is floodfed by gravity. The residence time of the material in the extruder wasapproximately two minutes. The extrudate was sheared into approximatelyone foot sections after exiting the die and placed on aluminum sheetsand allowed to cool at ambient conditions. After cooling, the extrudateswere milled with a ceramic mortar and pestle and passed through a 250 μmsieve.

Example 15

The following procedure is used for the preparation of HPMC-stabilizedamorphous ketoconazole particles using a solvent evaporation technology.

Formulation:

Component Quantity Ketoconazole (KCZ) 50% Methocel E5 (HPMC) 50%Dichloromethane 2 mL/g solids

Procedure:

Ketoconazole was dissolved into the organic solvent with the use of anAquasonic Model 150T ultrasonicator. The ketoconazole solution was thenadded into a glass mortar which contained the required amount of HPMC.Under a fume hood, the solution was well mixed with the HPMC powderusing a glass pestle until a colorless viscous gel was obtained. Most ofthe solvent was evaporated during this mixing process. The residualsolvent was then completely evaporated in a vacuum chamber attemperature of 40° C. and pressure of 500 mTorr to yield a dry solidproduct. The solid product was subsequently milled in a ceramic mediamill containing 20 to 30 ceramic milling balls one centimeter indiameter for approximately one hour at a mill RPM value of 40 to 50. Theresulting product was HPMC-stabilized amorphous ketoconazole particleswith individual particle diameters ranging from 2 to 50 μm.

Example 16

Hot-Melt Extrusion of Amorphous Fine Drug Particles of Ketoconazole

Because the fine drug particles described in Example 15 contain HPMC asa major constituent, which has a glass transition temperature in therange of 170 to 180° C., the amorphous microparticle complex willmaintain its integrity and thereby its amorphous state if extruded attemperatures of approximately 100° C. or below. The following is anexample of a hot-melt extrusion formulation and process by which ahomogenous extrudate of individualized and stabilized ketoconazole/HPMCamorphous microparticles can be produced.

Formulation:

Component Quantity Ketoconazole/HPMC E3 amorphous 50% microparticles(Example 15) Poloxamer 407 35% Sentry Poloyox WSR N80 (PEO) 15%

Process:

A Randcastle Microtruder RCP-0750 hot-melt extruder equipped with a 4 mmround die was operated at 20 RPM, 0.1-0.2 Drive Amps at a melttemperature of 60° C. to prepare the composition. All powders wereblended in a v-shell blender prior to extrusion. Temperature zones wereset as follows: zone 1: 40° C., zone 2: 60° C., zone 3: 60° C., dietemperature 60° C. The powder blend was placed in a hopper that islocated at the head of a vertical screw such that the material is floodfed by gravity. The residence time of the material in the extruder wasapproximately two minutes. The extrudate was sheared into approximatelyone foot sections after exiting the die and placed on aluminum sheetsand allowed to cool at ambient conditions.

Example 17

The following procedure is used for the preparation of crystallineDanazol nanoparticles by a wet milling technology.

Formulation:

Component Quantity Danazol (DNZ) 75% Polyvinylpyrrolidone 25% (PVP;grade K30) Deionized water 10 mL/g solids

Procedure:

All components listed in the table above were added to a size 000grinding mill jar (U.S. Stoneware, East Palestine, Ohio) along with 15,2 cm diameter cylindrical Zirconia grinding media. The grinding jar wascapped and allowed to turn on rollers at a rate of 50 RPM for 10 days.The resulting suspension of danazol nanoparticles in water was thenrapidly frozen by pouring into liquid nitrogen. The frozen particleswere then lyophilized in a VirTis AdVantage benchtop freeze dryer. Theresulting product was PVP-stabilized nanocrystals of Danazol withindividual particle diameters ranging from 1 μm to 50 nm.

Example 18

Hot-Melt Extrusion of Crystalline Danazol Nanoparticles

Because of the size of and the processing method use to prepare thecrystalline danazol nanoparticles, the particles produced are highlyaggregated. Therefore, the full benefit of particle size reduction isnot achieved by nanocrystal production alone. By melt extruding danazolnanocrystals with a carrier formulation and extrusion parameters that donot solubilize danazol, the stable crystalline form of the drug is notaltered and nanoparticle aggregates are broken up and dispersed asindividual nanoparticles within the hydrophilic, stabilizing extrudatecarrier. The following is an example of a hot-melt extrusion formulationand process by which a homogenous extrudate of individualized andstabilized danazol nanocrystals can be produced.

Formulation:

Component Quantity Danazol nanocrystals 50% (Example 17) Poloxamer 40735% Sentry Poloyox WSR 15% N80 (PEO)

Process:

A Randcastle Microtruder RCP-0750 hot-melt extruder equipped with a 4 mmround die was operated at 20 RPM, 0.1-0.2 Drive Amps at a melttemperature of 60° C. to prepare the composition. All powders wereblended in a v-shell blender prior to extrusion. Temperature zones wereset as follows: zone 1: 40° C., zone 2: 60° C., zone 3: 60° C., dietemperature 60° C. The powder blend was placed in a hopper that islocated at the head of a vertical screw such that the material is floodfed by gravity. The residence time of the material in the extruder wasapproximately two minutes. The extrudate was sheared into approximatelyone foot sections after exiting the die and placed on aluminum sheetsand allowed to cool at ambient conditions.

CITATIONS

-   1. Zhang, F. and J. W. McGinity, Properties of Sustained-Release    Tablets Prepared by Hot-Melt Extrusion. Pharmaceutical Development    and Technology, 1999. 4(2): p. 241-250.-   2. Zhang, F. and J. W. McGinity, Properties of Hot-Melt Extruded    Theophylline Tablets Containing Poly(Vinyl Acetate). Drug    Development and Industrial Pharmacy, 2000. 26(9): p. 931-942.-   3. Robinson, J. R., J. W. McGinity, and P. Delmas, Effervescent    granules and methods for their preparation. June 2000 and November    2003, Ethypharm: U.S. Pat. Nos. 6,071,539 and 6,649,186.-   4. Kothrade, S., et al., Method for producing solid dosing forms.    2003: U.S. Pat. No. 6,528,089 WO9927916 DE19753298 EP1035841.-   5. Aitken-Nichol, C., F. Zhang, and J. W. McGinity, Hot Melt    Extrusion of Acrylic Films. Pharmaceutical Research, 1996. 13(5): p.    804-808.-   6. Grabowski, S., et al., Solid active extrusion compound    preparations containing low-substituted hydroxypropylcellulose.    1999: U.S. Pat. No. 5,939,099 WO9625151 DE19504832 EP0809488.-   Repka, M. A. and J. W. McGinity, Hot-melt extruded films for    transmucosal & transdermal dung delivery applications. Drug Delivery    Technology, 2004. 4(7): p. 40, 42, 44-47.-   8. Repka, M. A., S. L. Repka, and J. W. McGinity, Bioadhesive    hot-melt extruded film for topical and mucosal adhesion applications    and drug delivery and process for preparation thereof. Apr. 23,    2002: U.S. Pat. No. 6,375,963.-   9. Breitenbach, J. and H. D. Zettler, Method for producing solid    sphereical materials containing a biologically active substance.    2000: WO 0024382.-   10. de Brabander, C., C. Vervaet, and J. P. Remon, Development and    evaluation of sustained release mini-matrices prepared via hot melt    extrusion. Journal of Controlled Release, 2003. 89(2): p. 235-247.-   11. de Brabander, C., et al., Bioavailability of ibuprofen from    hot-melt extruded mini-matrices. International Journal of    Pharmaceutics, 2004. 271(1-2): p. 77-84.-   12. Rosenberg, J. and J. Breitenbach, The production of active    substance compositions in the form of a solid solution of the active    substance in a polymer matrix, and active substance compositions    produced by this process. 1998: U.S. Pat. No. 5,741,519 WO 9629061    EP 0760654 DE 19509807.-   13. Six, K., et al., Characterization of Solid Dispersions of    Itraconazole and Hydroxypropylmethylcellulose Prepared by Melt    Extrusion, Part II. Pharmaceutical Research, 2003. 20(7): p.    1047-1054.-   14. Six, K., et al., Thermal Properties of Hot-Stage Extrudates of    Itraconazole and Eudragit E100Phase Separation and Polymorphism.    Journal of Thermal Analysis and calorimetry, 2002. 68: p. 591-601.-   15. Six, K., et al., Identification of Phase Separation in Solid    Dispersions of Itraconazole and Eudragit E100 Using Microthermal    Analysis. Pharmaceutical Research, 2003. 20(1): p. 135-138.-   16. Six, K., et al., Increased Physical Stability and Improved    Dissolution Properties of Itraconazole, a Class II Drug, by Solid    Dispersions that Combine Fast-and Slow-Dissolving Polymers. Journal    of Pharmaceutical Sciences, 2004. 93(1): p. 124-131.-   17. Verreck, G., et al., Characterization of solid dispersions of    itraconazole and hydroxypropylmethylcellulose prepared by melt    extrusion—part I. International Journal of Pharmaceutics, 2003.    251(1-2): p. 165-174.-   18. Brewster, M., et al., Solid dispersion comprising two different    polymer matrixes. 2004: WO2004004683.-   19. Baert, L. E. C., G. Verreck, and D. Thone, Antifungal    compositions with improved bioavailability. 2003: U.S. Pat. No.    6,509,038, WO9744014, U.S. Pat. No. 6,509,038 (B2), US2001007678    (A1), EE9800304 (A), TR9801225T (T2), EE3902 (B1).-   20. Rambali, B., et al., Itraconazole Formulation Studies of the    Melt-Extrusion Process with Mixture Design. Drug Development and    Industrial Pharmacy, 2003. 29(6): p. 641-652.-   21. Verreck, G., et al., The Use of Three Different Solid Dispersion    Formulations Melt Extrusion, Film-Coated Beads, and a Glass    Thermoplastic System—To Improve the Bioavailability of a Novel    Microsomal Triglyceride Transfer Protein Inhibitor. Journal of    Pharmaceutical Sciences, 2004. 93(5): p. 1217-1228.-   22. Hulsmann, S., et al., Melt extrusion—an alternative method for    enhancing the dissolution rate of 17(beta)-estradiol hemihydrate.    European Journal of Pharmaceutics and Biopharmaceutics, 2000.    49(3): p. 237-242.-   23. Forster, A., J. Hempenstall, and T. Rades, Characterization of    glass solutions of poorly water soluble drugs produced by melt    extrusion with hydrophilic amorphous polymers. Journal of Pharmacy    and Pharmacology, 2001. 53: p. 303-315.-   24. Kearney, A. S., et al., Effect of polyvinylpyrrolidone on the    crystallinity and dissolution rate of solid dispersions of the    antiinflammatory CI-987. International Journal of    Pharmaceutics, 1994. 104(2): p. 169-174.-   25. Nykamp, G., U. Carstensen, and B. W. Muller, Jet milling—a new    technique for microparticle preparation. International Journal of    Pharmaceutics, 2002. 242(1-2): p. 79-86.-   26. Carstensen, U. and B. W. Mueller, New process for the    preparation of microparticles, useful e.g. for controlled drug    release, comprises encapsulating active agent in biodegradable    polymer under heating, cooling and milling in two stages to a fine    powder. 2002: DE10061932.-   27. Reverchon, E., Supercritical antisolvent precipitation of    micro-and nano-particles. Journal of Supercritical Fluids,    The, 1999. 15(1): p. 1-21.-   28. Palakodaty, S. and P. York, Phase Behavioral Effects on Particle    Formation Processes Using Supercritical Fluids. Pharmaceutical    Research, 1999. 16(7): p. 976-985.-   29. Bleich, J. and B. W. Mueller, Production of drug loaded    microparticles by the use of supercritical gases with the Aerosol    Solvent Extraction System (ASES) process. Journal of    Microencapsulation, 1996. 13(2): p. 131-139.-   30. Chen, X., et al., Preparation of cyclosporine A nanoparticles by    evaporative precipitation into aqueous solution. International    Journal of Pharmaceutics, 2002. 242(1-2): p. 3-14.-   31. Chattopadhyay, P. and R. B. Gupta, Production of griseofulvin    nanoparticles using supercritical CO2 antisolvent with enhanced mass    transfer. International Journal of Pharmaceutics, 2001. 228(1-2): p.    19-31.-   32. Ghaderi, R., P. Artursson, and J. Carlfors, Preparation of    biodegradable microparticles using solution-enhanced dispersion by    supercritical fluids (SEDS). Pharmaceutical research, 1999.    16(6): p. 676-681.-   33. Phillips, E. M. and V. J. Stella, Rapid expansion from    supercritical solutions: application to pharmaceutical processes.    International Journal of Pharmaceutics, 1993. 94(1-3): p. 1-10.-   34. Hu, J., et al., Improvement of Dissolution Rates of Poorly Water    Soluble APIs Using Novel Spray Freezing into Liquid Technology.    Pharmaceutical Research, 2002. 19(9): p. 1278-1284.-   35. Evans, J. C., et al., Preparation of nanostructured particles of    poorly water soluble drugs via a novel ultra-rapid freezing    technology. Polymeric Materials Science and Engineering    (2003), 2003. 89: p. 742.-   36. Zimon, A. D., Adhesion of Dust and Powder. 1982, New York:    Consultants Bureau (Plenum). pp 93-144.-   37. French, D. L., D. A. Edwards, and R. W. Niven, The influence of    formulation of emission, deaggregation and deposition of dry powders    for inhalation. Journal of Aerosol Science, 1996. 27: p. 769-783.-   38. Liu, J. and P. J. Stewart, Deaggregation during the Dissolution    of Benzodiazepines in Interactive Mixtures. Journal of    Pharmaceutical Science, 1998. 87(12): p. 1632-1638.-   39. Ticehurst, M. D., et al., Characterisation of the influence of    micronisation on the crystallinity and physical stability of    revatropate hydrobromide. International Journal of    Pharmaceutics, 2000. 193: p. 247-259.-   40. Hu, J., K. P. Johnston, and I. Williams, Robert O., Rapid    release tablet formulation of micronized danazol powder produced by    spray-freezing into liquid (SFL). Journal of Drug Delivery Science    and Technology, 2004. 14(4): p. 305-311.-   41. Liversidge, G. G. and P. Conzentino, Drug particle size    reduction for decreasing gastric irritancy and enhancing absorption    of naproxen in rats. International Journal of Pharmaceutics, 1995.    125(2): p. 309-313.-   42. Liversidge, G. G. and K. C. Cundy, Particle size reduction for    improvement of oral bioavailability of hydrophobic drugs. Part 1:    Absolute oral bioavailability of nanocrystalline danazol in beagle    dogs. International Journal of Pharmaceutics, 1995. 125: p. 91-97.

The above is a detailed description of particular embodiments of theinvention. It will be appreciated that, although specific embodiments ofthe invention have been described herein for purposes of illustration,various modifications may be made without departing from the spirit andscope of the invention. Accordingly, the invention is not limited exceptas by the appended claims. All of the embodiments disclosed and claimedherein can be made and executed without undue experimentation in lightof the present disclosure.

1.-19. (canceled)
 20. A process for preparing a hot-melt extrudedpharmaceutical composition comprising drug-containing particlesdispersed in a stabilizing and non-solubilizing carrier, the processcomprising: providing drug-containing particles of a therapeuticcompound, wherein said particles have a mean particle diameter of 100microns or less and comprise one or more amorphous or crystallinetherapeutic compounds dispersed in one or more adjunct stabilizers;admixing said drug-containing particles with a stabilizing andnon-solubilizing hot-melt extrudable carrier that does not solubilize,or solubilizes 10% drug weight or less of, the drug containing particlesto form a particle-carrier admixture; and mixing and hot-meltingextruding the charges particle-carrier admixture to form the hot-meltextruded pharmaceutical composition; wherein a substantial majority ofthe fine drug particles are not agglomerated or aggregated as a resultof the step of hot-melt extruding.
 21. The process of claim 20 furthercomprising: preparing the fine drug-containing particles by mechanicalmilling; solution based phase separation technique; freezing techniqueor a combination thereof.
 22. The process of claim 21 furthercomprising: preparing the fine drug-containing particles by ball mill,jet mill, grinding, mortar and pestle grinding, spray drying, combinedemulsification and evaporation, combined emulsification and solventextraction, complex coacervation, gas antisolvent precipitation,precipitation with a compressed antisolvent, aerosol solvent extractionsystem, evaporative precipitation into aqueous solution, supercriticalantisolvent, solution-enhanced dispersion by supercritical fluids, rapidexpansion from supercritical to aqueous solutions, pressure inducedphase separation, spray freezing into liquid, ultra rapid freezing,anti-solvent precipitation or a combination thereof.
 23. The process ofclaim 20, the process further comprising: determining the temperature atwhich the therapeutic compound dissolves into the stabilizing andnon-solubilizing hot-melt extrudable carrier; and/or determining thetemperature at which amorphous drug in the fine drug-containingparticles begins to recrystallize.
 24. The process of claim 23, whereinthe therapeutic compound is amorphous, and the step of hot-meltextruding is conducted at a temperature that is at least 10° C. belowthe temperature at which the therapeutic compound in the finedrug-containing particles begins to recrystallize.
 25. The process ofclaim 24, wherein the step of hot-melt extruding is conducted at atemperature wherein the stabilizing and non-solubilizing hot-meltextrudable carrier melts.
 26. The process of claim 23, wherein thetherapeutic compound is crystalline, and the step of hot-melt extrudingis conducted at a temperature that is at least 10° C. below thetemperature at which the therapeutic compound dissolves into thestabilizing and non-solubilizing hot-melt extrudable carrier.
 27. Theprocess of claim 26, wherein the step of hot-melt extruding is conductedat a temperature wherein the stabilizing and non-solubilizing hot-meltextrudable carrier melts.
 28. The process of claim 20, wherein thedrug-containing particles comprise a therapeutic compound and one ormore adjunct stabilizers.
 29. The process of claim 28, wherein theadjunct stabilizer is selected from the group consisting of sorbitanesters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylenealkyl ethers, poloxamers (polyethylene-polypropylene glycol blockcopolymers), sucrose esters, sodium lauryl sulfate, oleic acid, lauricacid, vitamin E TPGS, polyoxyethylated glycolysed glycerides,dipalmitoyl phosphadityl choline, glycolic acid and salts, deoxycholicacid and salts, sodium fusidate, cyclodextrins, polyethylene glycols,polyglycolyzed glycerides, polyvinyl alcohols, polyacrylates,polymethacrylates, polyvinylpyrrolidones, phosphatidyl choline andderivatives, and cellulose derivatives and a combination thereof. 30.The process of claim 29, wherein the adjunct stabilizer is comprised ofa polyvinylpyrrolidone.
 31. The process of claim 20, wherein thestabilizing and non-solubilizing carrier is selected from the groupconsisting of a poloxamer, polyethylene oxide; polypropylene oxide;polyvinylpyrrolidone; polyvinylpyrrolidone-co-vinylacetate; acrylate andmethacrylate copolymers; polyethylene; polycaprolactone;polyethylene-co-polypropylene; alkylcellulose; hydroxyalkylcellulose;hydroxyalkyl alkylcellulose; starch; pectin; polysaccharide; lipid; wax;mono, di, and tri glycerides; cetyl alcohol; steryl alcohol; parafilmwax; hydrogenated vegetable and castor oil; glycerol monostearte;polyolefin; xylitol; mannitol; sorbitol; alpha-hydroxyl acid; entericpolymer; and a combination thereof.
 32. The process of claim 31, whereinthe stabilizing and non-solubilizing carrier is comprised ofpolyethylene oxide.
 33. The process of claim 20, wherein the particleshave a mean particle diameter of 50 microns or less.
 34. The process ofclaim 33, wherein the particles have a mean particle diameter of 10microns or less.
 35. The process of claim 20, wherein the particles havea mean particle diameter of 1 micron or less.
 36. The process of claim20, wherein greater than 75% of the particles have an average diameterof less than about 20 microns.
 37. The process of claim 36, whereingreater than 75% of the particles have an average diameter of less thanabout 5 microns.
 38. The process of claim 38, wherein greater than 75%of the particles have an average diameter of less than about 1 micron.39. The process of claim 20, wherein 5% by number or less of theparticles are present in the composition in agglomerated form.
 40. Theprocess of claim 20, wherein the fine particles have been prepared byspray drying, mechanical milling, solution based phase separationtechnique, freezing technique, anti-solvent precipitation, or acombination thereof.
 41. The process of claim 40, wherein the fineparticles have been prepared by spray drying.
 42. The process of claim20, wherein the therapeutic compound is amorphous.
 43. The process ofclaim 42, which has been hot-melt extruded at a temperature that is atleast 10° C. below the temperature at which the therapeutic compound inthe fine particles begins to recrystallize.
 44. The process of claim 20,wherein the therapeutic compound is crystalline.
 45. The process ofclaim 44, which has been hot-melt extruded at a temperature that is atleast 10° C. below the temperature at which the therapeutic compounddissolves into the stabilizing and non-solubilizing hot-melt extrudablecarrier.
 46. The process of claim 20, wherein the composition has beenhot-melt extruded at a temperature that is 100° C. or less.
 47. Theprocess of claim 20, wherein the therapeutic compound is itraconazole.